Targeting tumour-supportive cellular machineries in anticancer drug development

Nature Reviews Drug Discovery

Volumn 13, Issue 3, 2014, Pages 179-196

  Dobbelstein, Matthias ^a   Moll, Ute ^b  

^a UNIVERSITY MEDICAL CENTER GÖTTINGEN   (Germany)

^b STONY BROOK UNIVERSITY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ANTINEOPLASTIC AGENT; BEVACIZUMAB; BRENTUXIMAB VEDOTIN; CETUXIMAB; GEFITINIB; IMATINIB; IPILIMUMAB; LAPATINIB; NIVOLUMAB; PAZOPANIB; RITUXIMAB; SORAFENIB; SUNITINIB; TIVANTINIB; TRASTUZUMAB; VEMURAFENIB; VISMODEGIB;

B CELL LYMPHOMA; BASAL CELL CARCINOMA; BREAST CANCER; BREAST METASTASIS; CANCER CHEMOTHERAPY; CANCER RESISTANCE; CELL KINETICS; CHROMOSOME SEGREGATION; CHRONIC MYELOID LEUKEMIA; COLORECTAL CANCER; DNA REPAIR; DNA REPLICATION; DRUG EFFECT; DRUG EFFICACY; DRUG INDICATION; DRUG RESEARCH; DRUG TARGETING; FOLLICULAR LYMPHOMA; HEAD AND NECK CANCER; HODGKIN DISEASE; HUMAN; KIDNEY CARCINOMA; LARGE CELL LYMPHOMA; LIVER CELL CARCINOMA; LUNG NON SMALL CELL CANCER; M PHASE CELL CYCLE CHECKPOINT; MALIGNANT NEOPLASTIC DISEASE; MEDULLOBLASTOMA; MELANOMA; NONHUMAN; PRIORITY JOURNAL; PROTEIN CONFORMATION; PROTEIN FOLDING; REVIEW; SIGNAL TRANSDUCTION; SOFT TISSUE SARCOMA; TREATMENT DURATION;

ANIMALS; ANTIBODIES, MONOCLONAL; ANTINEOPLASTIC AGENTS; CHROMATIN; DRUG DELIVERY SYSTEMS; DRUG DISCOVERY; HEAT-SHOCK PROTEINS; HUMANS; NEOPLASMS; NEOPLASTIC CELLS, CIRCULATING; SIGNAL TRANSDUCTION;

EID: 84895836004     PISSN: 14741776     EISSN: 14741784     Source Type: Journal    
DOI: 10.1038/nrd4201     Document Type: Review

References (305)

1. Goodman, L. S. et al. Nitrogen mustard therapy; use of methyl-bis (beta-chloroethyl) amine hydrochloride and tris (beta-chloroethyl) amine hydrochloride for Hodgkin's disease, lymphosarcoma, leukemia and certain allied and miscellaneous disorders. JAMA 132, 126-132 (1946
2. Gilman, A. & Philips, F. S. The biological actions and therapeutic applications of the B chloroethyl amines and sulfides. Science 103, 409-415 (1946
3. Mukherjee, S. The Emperor of All Maladies: A Biography of Cancer (Scribner, 2010
4. Jackson, J. R., Patrick, D. R., Dar, M. M. & Huang, P. S. Targeted anti-mitotic therapies: Can we improve on tubulin agents? Nature Rev. Cancer 7, 107-117 (2007
5. Armstrong, G. T. et al. Occurrence of multiple subsequent neoplasms in long-Term survivors of childhood cancer: A report from the childhood cancer survivor study. J. Clin. Oncol. 29, 3056-3064 (2011
6. Travis, L. B. et al. Second cancers among 40,576 testicular cancer patients: Focus on long-Term survivors. J. Natl Cancer Inst. 97, 1354-1365 (2005
7. Strebhardt, K. & Ullrich, A. Paul Ehrlich's magic bullet concept: 100 years of progress. Nature Rev. Cancer 8, 473-480 (2008
8. Luo, J., Solimini, N. L. & Elledge, S. J. Principles of cancer therapy: Oncogene and non-oncogene addiction. Cell 136, 823-837 (2009
9. Felsher, D. W. MYC inactivation elicits oncogene addiction through both tumor cell-intrinsic and host-dependent mechanisms. Genes Cancer 1, 597-604 (2010
10. Capdeville, R., Buchdunger, E., Zimmermann, J. & Matter, A. Glivec (STI571, imatinib), a rationally developed, targeted anticancer drug. Nature Rev. Drug Discov. 1, 493-502 (2002
11. Vogel, C. L. et al. Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2 overexpressing metastatic breast cancer. J. Clin. Oncol. 20, 719-726 (2002
12. Ashwell, S. & Zabludoff, S. DNA damage detection and repair pathways-recent advances with inhibitors of checkpoint kinases in cancer therapy. Clin. Cancer Res. 14, 4032-4037 (2008
13. Guertin, D. A. & Sabatini, D. M. Defining the role of mTOR in cancer. Cancer Cell 12, 9-22 (2007
14. Sierra, J. R., Cepero, V. & Giordano, S. Molecular mechanisms of acquired resistance to tyrosine kinase targeted therapy. Mol. Cancer 9, 75 (2010
15. Milojkovic, D. & Apperley, J. Mechanisms of resistance to imatinib and second-generation tyrosine inhibitors in chronic myeloid leukemia. Clin. Cancer Res. 15, 7519-7527 (2009
16. Druker, B. J. et al. Five-year follow up of patients receiving imatinib for chronic myeloid leukemia. N. Engl. J. Med. 355, 2408-2417 (2006
17. Grebien, F. et al. Targeting the SH2 kinase interface in Bcr-Abl inhibits leukemogenesis. Cell 147, 306-319 (2011
18. Chan, W. W. et al. Conformational control inhibition of the BCR ABL1 tyrosine kinase, including the gatekeeper T315I mutant, by the switch-control inhibitor DCC 2036. Cancer Cell 19, 556-568 (2011
19. Zhang, J. et al. Targeting Bcr-Abl by combining allosteric with ATP-binding-site inhibitors. Nature 463, 501-506 (2010
20. Gregory, M. A. et al. Wnt/Ca2+/NFAT signaling maintains survival of Ph+ leukemia cells upon inhibition of Bcr-Abl. Cancer Cell 18, 74-87 (2010
21. Naka, K. et al. TGF-β-FOXO signalling maintains leukaemia-initiating cells in chronic myeloid leukaemia. Nature 463, 676-680 (2010
22. Villamor, N., Montserrat, E. & Colomer, D. Mechanism of action and resistance to monoclonal antibody therapy. Seminars Oncol. 30, 424-433 (2003
23. Berns, K. et al. A functional genetic approach identifies the PI3K pathway as a major determinant of trastuzumab resistance in breast cancer. Cancer Cell 12, 395-402 (2007
24. Pohlmann, P. R., Mayer, I. A. & Mernaugh, R. Resistance to trastuzumab in breast cancer. Clin. Cancer Res. 15, 7479-7491 (2009
25. Nahta, R., Yu, D., Hung, M. C., Hortobagyi, G. N. & Esteva, F. J. Mechanisms of disease: Understanding resistance to HER2 targeted therapy in human breast cancer. Nature Clin. Pract. Oncol. 3, 269-280 (2006
26. Knight, Z. A., Lin, H. & Shokat, K. M. Targeting the cancer kinome through polypharmacology. Nature Rev. Cancer 10, 130-137 (2010
27. Apsel, B. et al. Targeted polypharmacology: Discovery of dual inhibitors of tyrosine and phosphoinositide kinases. Nature Chem. Biol. 4, 691-699 (2008
28. Furge, K. A., MacKeigan, J. P. & Teh, B. T. Kinase targets in renal-cell carcinomas: Reassessing the old and discovering the new. Lancet Oncol. 11, 571-578 (2010
29. Flaherty, K. T. et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N. Engl. J. Med. 367, 1694-1703 (2012
30. Spigel, D. R. et al. Randomized, double-blind, placebo-controlled, phase II trial of sorafenib and erlotinib or erlotinib alone in previously treated advanced non-small-cell lung cancer. J. Clin. Oncol. 29, 2582-2589 (2011
31. Sequist, L. V. et al. Randomized phase II study of erlotinib plus tivantinib versus erlotinib plus placebo in previously treated non-small-cell lung cancer. J. Clin. Oncol. 29, 3307-3315 (2011
32. Vogelstein, B. et al. Cancer genome landscapes. Science 339, 1546-1558 (2013
33. Hanahan, D. & Weinberg, R. A. The hallmarks of cancer. Cell 100, 57-70 (2000
34. Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: The next generation. Cell 144, 646-674 (2011
35. Taipale, M., Jarosz, D. F. & Lindquist, S. HSP90 at the hub of protein homeostasis: Emerging mechanistic insights. Nature Rev. Mol. Cell Biol. 11, 515-528 (2010
36. Dai, C., Dai, S. & Cao, J. Proteotoxic stress of cancer: Implication of the heat-shock response in oncogenesis. J. Cell. Physiol. 227, 2982-2987 (2012
37. Stadtman, E. R. Protein oxidation in aging and age-related diseases. Ann. NY Acad. Sci. 928, 22-38 (2001
38. Trepel, J., Mollapour, M., Giaccone, G. & Neckers, L. Targeting the dynamic HSP90 complex in cancer. Nature Rev. Cancer 10, 537-549 (2010
39. Terzian, T. et al. The inherent instability of mutant p53 is alleviated by Mdm2 or p16INK4a loss. Genes Dev. 22, 1337-1344 (2008
40. Li, D., Marchenko, N. D. & Moll, U. M. SAHA shows preferential cytotoxicity in mutant p53 cancer cells by destabilizing mutant p53 through inhibition of the HDAC6-Hsp90 chaperone axis. Cell Death Differ. 18, 1904-1913 (2011
41. Li, D. et al. Functional inactivation of endogenous MDM2 and CHIP by HSP90 causes aberrant stabilization of mutant p53 in human cancer cells. Mol. Cancer Res. 9, 577-588 (2011
42. Sato, S., Fujita, N. & Tsuruo, T. Modulation of Akt kinase activity by binding to Hsp90. Proc. Natl Acad. Sci. USA 97, 10832-10837 (2000
43. Whitesell, L. & Lindquist, S. L. HSP90 and the chaperoning of cancer. Nature Rev. Cancer 5, 761-772 (2005
44. Kamal, A. et al. A high-Affinity conformation of Hsp90 confers tumour selectivity on Hsp90 inhibitors. Nature 425, 407-410 (2003
45. De Raedt, T. et al. Exploiting cancer cell vulnerabilities to develop a combination therapy for ras-driven tumors. Cancer Cell 20, 400-413 (2011
46. Chen, G., Bradford, W. D., Seidel, C. W. & Li, R. Hsp90 stress potentiates rapid cellular adaptation through induction of aneuploidy. Nature 482, 246-250 (2012
47. Cerchietti, L. C. et al. A purine scaffold Hsp90 inhibitor destabilizes BCL 6 and has specific antitumor activity in BCL 6 dependent B cell lymphomas. Nature Med. 15, 1369-1376 (2009
48. Schulz, R. et al. Inhibiting the HSP90 chaperone destabilizes macrophage migration inhibitory factor and thereby inhibits breast tumor progression. J. Exp. Med. 209, 275-289 (2012
49. Modi, S. et al. HSP90 inhibition is effective in breast cancer: A phase II trial of tanespimycin (17 AAG) plus trastuzumab in patients with HER2 positive metastatic breast cancer progressing on trastuzumab. Clin. Cancer Res. 17, 5132-5139 (2011
50. Leu, J. I., Pimkina, J., Frank, A., Murphy, M. E. & George, D. L. A small molecule inhibitor of inducible heat shock protein 70. Mol. Cell 36, 15-27 (2009
51. Dorard, C. et al. Expression of a mutant HSP110 sensitizes colorectal cancer cells to chemotherapy and improves disease prognosis. Nature Med. 17, 1283-1289 (2011
52. Adams, J. The proteasome: A suitable antineoplastic target. Nature Rev. Cancer 4, 349-360 (2004
53. Inuzuka, H. et al. SCF(FBW7) regulates cellular apoptosis by targeting MCL1 for ubiquitylation and destruction. Nature 471, 104-109 (2011
54. Wertz, I. E. et al. Sensitivity to antitubulin chemotherapeutics is regulated by MCL1 and FBW7. Nature 471, 110-114 (2011
55. Nijhawan, D. et al. Cancer vulnerabilities unveiled by genomic loss. Cell 150, 842-854 (2012
56. Luo, J. et al. A genome-wide RNAi screen identifies multiple synthetic lethal interactions with the Ras oncogene. Cell 137, 835-848 (2009
57. Groll, M., Berkers, C. R., Ploegh, H. L. & Ovaa, H. Crystal structure of the boronic acid-based proteasome inhibitor bortezomib in complex with the yeast 20S proteasome. Structure 14, 451-456 (2006
58. Parlati, F. et al. Carfilzomib can induce tumor cell death through selective inhibition of the chymotrypsin-like activity of the proteasome. Blood 114, 3439-3447 (2009
59. Richardson, P. G. et al. Extended follow up of a phase 3 trial in relapsed multiple myeloma: Final time to event results of the APEX trial. Blood 110, 3557-3560 (2007
60. Vij, R. et al. An open-label, single-Arm, phase 2 (PX 171 004) study of single-Agent carfilzomib in bortezomib-naive patients with relapsed and/or refractory multiple myeloma. Blood 119, 5661-5670 (2012
61. D'Arcy, P. et al. Inhibition of proteasome deubiquitinating activity as a new cancer therapy. Nature Med. 17, 1636-1640 (2011
62. Lee, B. H. et al. Enhancement of proteasome activity by a small-molecule inhibitor of USP14. Nature 467, 179-184 (2010
63. Ceccarelli, D. F. et al. An allosteric inhibitor of the human Cdc34 ubiquitin-conjugating enzyme. Cell 145, 1075-1087 (2011
64. Soucy, T. A. et al. An inhibitor of NEDD8 activating enzyme as a new approach to treat cancer. Nature 458, 732-736 (2009
65. Chauhan, D. et al. A small molecule inhibitor of ubiquitin-specific protease 7 induces apoptosis in multiple myeloma cells and overcomes bortezomib resistance. Cancer Cell 22, 345-358 (2012
66. Stresemann, C. & Lyko, F. Modes of action of the DNA methyltransferase inhibitors azacytidine and decitabine. Int. J. Cancer 123, 8-13 (2008
67. Issa, J. P., Kantarjian, H. M. & Kirkpatrick, P. Azacitidine. Nature Rev. Drug Discov. 4, 275-276 (2005
68. Kantarjian, H. et al. Decitabine improves patient outcomes in myelodysplastic syndromes: Results of a phase III randomized study. Cancer 106, 1794-1803 (2006
69. Bolden, J. E., Peart, M. J. & Johnstone, R. W. Anticancer activities of histone deacetylase inhibitors. Nature Rev. Drug Discov. 5, 769-784 (2006
70. Minucci, S. & Pelicci, P. G. Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer. Nature Rev. Cancer 6, 38-51 (2006
71. Mann, B. S., Johnson, J. R., Cohen, M. H., Justice, R. & Pazdur, R. FDA approval summary: Vorinostat for treatment of advanced primary cutaneous T cell lymphoma. Oncol. 12, 1247-1252 (2007
72. Coiffier, B. et al. Results from a pivotal, open-label, phase II study of romidepsin in relapsed or refractory peripheral T cell lymphoma after prior systemic therapy. J. Clin. Oncol. 30, 631-636 (2012
73. Beyer, U., Moll-Rocek, J., Moll, U. M. & Dobbelstein, M. Endogenous retrovirus drives hitherto unknown proapoptotic p63 isoforms in the male germ line of humans and great apes. Proc. Natl Acad. Sci. USA 108, 3624-3629 (2011
74. Dawson, M. A. et al. Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia. Nature 478, 529-533 (2011
75. Delmore, J. E. et al. BET bromodomain inhibition as a therapeutic strategy to target c Myc. Cell 146, 904-917 (2011
76. Mertz, J. A. et al. Targeting MYC dependence in cancer by inhibiting BET bromodomains. Proc. Natl Acad. Sci. USA 108, 16669-16674 (2011
77. Filippakopoulos, P. et al. Selective inhibition of BET bromodomains. Nature 468, 1067-1073 (2010
78. Zuber, J. et al. RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia. Nature 478, 524-528 (2011
79. Albert, M. & Helin, K. Histone methyltransferases in cancer. Seminars Cell Dev. Biol. 21, 209-220 (2010
80. Varambally, S. et al. Genomic loss of microRNA 101 leads to overexpression of histone methyltransferase EZH2 in cancer. Science 322, 1695-1699 (2008
81. Knutson, S. K. et al. A selective inhibitor of EZH2 blocks H3K27 methylation and kills mutant lymphoma cells. Nature Chem. Biol. 8, 890-896 (2012
82. McCabe, M. T. et al. EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2 activating mutations. Nature 492, 108-112 (2012
83. Qi, W. et al. Selective inhibition of Ezh2 by a small molecule inhibitor blocks tumor cells proliferation. Proc. Natl Acad. Sci. USA 109, 21360-21365 (2012
84. Knutson, S. K. et al. Durable tumor regression in genetically altered malignant rhabdoid tumors by inhibition of methyltransferase EZH2. Proc. Natl Acad. Sci. USA 110, 7922-7927 (2013
85. Wilson, B. G. et al. Epigenetic antagonism between polycomb and SWI/SNF complexes during oncogenic transformation. Cancer Cell 18, 316-328 (2010
86. Sharma, S. V. et al. A chromatin-mediated reversible drug-Tolerant state in cancer cell subpopulations. Cell 141, 69-80 (2010
87. Zender, L. et al. An oncogenomics-based in vivo RNAi screen identifies tumor suppressors in liver cancer. Cell 135, 852-864 (2008
88. Zender, L. et al. Identification and validation of oncogenes in liver cancer using an integrative oncogenomic approach. Cell 125, 1253-1267 (2006
89. Pepperkok, R. & Ellenberg, J. High-Throughput fluorescence microscopy for systems biology. Nature Rev. Mol. Cell Biol. 7, 690-696 (2006
90. Scheffner, M., Werness, B. A., Huibregtse, J. M., Levine, A. J. & Howley, P. M. The E6 oncoprotein encoded by human papillomavirus types 16 and 18 promotes the degradation of p53. Cell 63, 1129-1136 (1990
91. Blachere, N. E. et al. Heat shock protein-peptide complexes, reconstituted in vitro, elicit peptide-specific cytotoxic T lymphocyte response and tumor immunity. J. Exp. Med. 186, 1315-1322 (1997
92. Mann, J. Natural products in cancer chemotherapy: Past, present and future. Nature Rev. Cancer 2, 143-148 (2002
93. Pommier, Y. & Marchand, C. Interfacial inhibitors: Targeting macromolecular complexes. Nature Rev. Drug Discov. 11, 25-36 (2012
94. Sali, A., Glaeser, R., Earnest, T. & Baumeister, W. From words to literature in structural proteomics. Nature 422, 216-225 (2003
95. Will, C. L. & Lührmann, R. Spliceosome structure and function. Cold Spring Harb. Perspect. Biol. 3, a003707 (2011
96. Bonnal, S., Vigevani, L. & Valcarcel, J. The spliceosome as a target of novel antitumour drugs. Nature Rev. Drug Discov. 11, 847-859 (2012
97. Schreiber, S. L. et al. Towards patient-based cancer therapeutics. Nature Biotech. 28, 904-906 (2010
98. Chen, Z. et al. A murine lung cancer co clinical trial identifies genetic modifiers of therapeutic response. Nature 483, 613-617 (2012
99. Goldman, J. W. et al. A first in human, safety, pharmacokinetics, and clinical activity phase I study of once weekly administration of the Hsp90 inhibitor ganetespib (STA 9090) in patients with solid malignancies. BMC Cancer 13, 152 (2013
100. Ramanathan, R. K. et al. Phase I pharmacokinetic-pharmacodynamic study of 17-(allylamino)-17 demethoxygeldanamycin (17AAG, NSC 330507), a novel inhibitor of heat shock protein 90, in patients with refractory advanced cancers. Clin. Cancer Res. 11, 3385-3391 (2005
101. Grem, J. L. et al. Phase I and pharmacologic study of 17-(allylamino)-17 demethoxygeldanamycin in adult patients with solid tumors. J. Clin. Oncol. 23, 1885-1893 (2005
102. Richardson, P. G. et al. Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N. Engl. J. Med. 352, 2487-2498 (2005
103. Chen, J. et al. A restricted cell population propagates glioblastoma growth after chemotherapy. Nature 488, 522-526 (2012
104. Balko, J. M. et al. Profiling of residual breast cancers after neoadjuvant chemotherapy identifies DUSP4 deficiency as a mechanism of drug resistance. Nature Med. 18, 1052-1059 (2012
105. Gupta, P. B. et al. Identification of selective inhibitors of cancer stem cells by high-Throughput screening. Cell 138, 645-659 (2009
106. Gupta, P. B., Chaffer, C. L. & Weinberg, R. A. Cancer stem cells: Mirage or reality? Nature Med. 15, 1010-1012 (2009
107. Garnett, M. J. et al. Systematic identification of genomic markers of drug sensitivity in cancer cells. Nature 483, 570-575 (2012
108. Barretina, J. et al. The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity. Nature 483, 603-607 (2012
109. Tredan, O., Galmarini, C. M., Patel, K. & Tannock, I. F. Drug resistance and the solid tumor microenvironment. J. Natl Cancer Inst. 99, 1441-1454 (2007
110. Provenzano, P. P. et al. Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma. Cancer Cell 21, 418-429 (2012
111. Olive, K. P. et al. Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science 324, 1457-1461 (2009
112. Yauch, R. L. et al. A paracrine requirement for hedgehog signalling in cancer. Nature 455, 406-410 (2008
113. Ahmed, F., Steele, J. C., Herbert, J. M., Steven, N. M. & Bicknell, R. Tumor stroma as a target in cancer. Curr. Cancer Drug Targets 8, 447-453 (2008
114. Kelloff, G. J. & Sigman, C. C. Cancer biomarkers: Selecting the right drug for the right patient. Nature Rev. Drug Discov. 11, 201-214 (2012
115. Vogelstein, B. & Kinzler, K. W. Cancer genes and the pathways they control. Nature Med. 10, 789-799 (2004
116. Walther, A. et al. Genetic prognostic and predictive markers in colorectal cancer. Nature Rev. Cancer 9, 489-499 (2009
117. McShane, L. M. et al. REporting recommendations for tumor MARKer prognostic studies (REMARK). Nature Clin. Pract. Urol. 2, 416-422 (2005
118. Kastan, M. B. & Bartek, J. Cell-cycle checkpoints and cancer. Nature 432, 316-323 (2004
119. Zhou, B. B. & Bartek, J. Targeting the checkpoint kinases: Chemosensitization versus chemoprotection. Nature Rev. Cancer 4, 216-225 (2004
120. Sabatini, D. M. mTOR and cancer: Insights into a complex relationship. Nature Rev. Cancer 6, 729-734 (2006
121. Garcia, M. A. et al. Impact of protein kinase PKR in cell biology: From antiviral to antiproliferative action. Microbiol. Mol. Biol. Rev. 70, 1032-1060 (2006
122. Farassati, F., Yang, A. D. & Lee, P. W. Oncogenes in Ras signalling pathway dictate host-cell permissiveness to herpes simplex virus 1. Nature Cell Biol. 3, 745-750 (2001
123. Strong, J. E., Coffey, M. C., Tang, D., Sabinin, P. & Lee, P. W. The molecular basis of viral oncolysis: Usurpation of the Ras signaling pathway by reovirus. EMBO J. 17, 3351-3362 (1998
124. Chlebowski, R. T. et al. Breast cancer after use of estrogen plus progestin in postmenopausal women. N. Engl. J. Med. 360, 573-587 (2009
125. Levine, A. J. & Oren, M. The first 30 years of p53: Growing ever more complex. Nature Rev. Cancer 9, 749-758 (2009
126. Bandyopadhyay, D., Mishra, A. & Medrano, E. E. Overexpression of histone deacetylase 1 confers resistance to sodium butyrate-mediated apoptosis in melanoma cells through a p53 mediated pathway. Cancer Res. 64, 7706-7710 (2004
127. Fantin, V. R. & Richon, V. M. Mechanisms of resistance to histone deacetylase inhibitors and their therapeutic implications. Clin. Cancer Res. 13, 7237-7242 (2007
128. Oerlemans, R. et al. Molecular basis of bortezomib resistance: Proteasome subunit beta5 (PSMB5) gene mutation and overexpression of PSMB5 protein. Blood 112, 2489-2499 (2008
129. Kaelin, W. G. Jr. The concept of synthetic lethality in the context of anticancer therapy. Nature Rev. Cancer 5, 689-698 (2005
130. Davies, J. & Davies, D. Origins and evolution of antibiotic resistance. Microbiol. Mol. Biol. Rev. 74, 417-433 (2010
131. Lukas, J., Lukas, C. & Bartek, J. More than just a focus: The chromatin response to DNA damage and its role in genome integrity maintenance. Nature Cell Biol. 13, 1161-1169 (2011
132. Luijsterburg, M. S. & van Attikum, H. Chromatin and the DNA damage response: The cancer connection. Mol. Oncol. 5, 349-367 (2011
133. Prenzel, T. et al. Estrogen-dependent gene transcription in human breast cancer cells relies upon proteasome-dependent monoubiquitination of histone H2B. Cancer Res. 71, 5739-5753 (2011
134. Fotheringham, S. et al. Genome-wide loss of function screen reveals an important role for the proteasome in HDAC inhibitor-induced apoptosis. Cancer Cell 15, 57-66 (2009
135. Kovacs, J. J. et al. HDAC6 regulates Hsp90 acetylation and chaperone-dependent activation of glucocorticoid receptor. Mol. Cell 18, 601-607 (2005
136. Bouwman, P. & Jonkers, J. The effects of deregulated DNA damage signalling on cancer chemotherapy response and resistance. Nature Rev. Cancer 12, 587-598 (2012
137. Savage, P., Stebbing, J., Bower, M. & Crook, T. Why does cytotoxic chemotherapy cure only some cancers? Nature Clin. Pract. Oncol. 6, 43-52 (2009
138. Edwards, S. L. et al. Resistance to therapy caused by intragenic deletion in BRCA2. Nature 451, 1111-1115 (2008
139. Gibson, B. A. & Kraus, W. L. New insights into the molecular and cellular functions of poly(ADP-ribose) and PARPs. Nature Rev. Mol. Cell Biol. 13, 411-424 (2012
140. Rouleau, M., Patel, A., Hendzel, M. J., Kaufmann, S. H. & Poirier, G. G. PARP inhibition: PARP1 and beyond. Nature Rev. Cancer 10, 293-301 (2010
141. Bryant, H. E. et al. Specific killing of BRCA2 deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature 434, 913-917 (2005
142. Johnson, N. et al. Compromised CDK1 activity sensitizes BRCA-proficient cancers to PARP inhibition. Nature Med. 17, 875-882 (2011
143. Curtin, N. J. DNA repair dysregulation from cancer driver to therapeutic target. Nature Rev. Cancer 12, 801-817 (2012
144. Kopper, F. et al. Damage-induced DNA replication stalling relies on MAPK-Activated protein kinase 2 activity. Proc. Natl Acad. Sci. USA 110, 16856-16861 (2013
145. Kaestner, P. & Bastians, H. Mitotic drug targets. J. Cell. Biochem. 111, 258-265 (2010
146. Jordan, M. A. & Wilson, L. Microtubules as a target for anticancer drugs. Nature Rev. Cancer 4, 253-265 (2004
147. Domingo-Domenech, J. et al. Suppression of acquired docetaxel resistance in prostate cancer through depletion of Notch-And Hedgehog-dependent tumor-initiating cells. Cancer Cell 22, 373-388 (2012
148. Zeng, X. et al. Pharmacologic inhibition of the anaphase-promoting complex induces a spindle checkpoint-dependent mitotic arrest in the absence of spindle damage. Cancer Cell 18, 382-395 (2010
149. Huang, H. C., Shi, J., Orth, J. D. & Mitchison, T. J. Evidence that mitotic exit is a better cancer therapeutic target than spindle assembly. Cancer Cell 16, 347-358 (2009
150. Kwon, M. et al. Mechanisms to suppress multipolar divisions in cancer cells with extra centrosomes. Genes Dev. 22, 2189-2203 (2008
151. Janssen, A., Kops, G. J. & Medema, R. H. Elevating the frequency of chromosome mis-segregation as a strategy to kill tumor cells. Proc. Natl Acad. Sci. USA 106, 19108-19113 (2009
152. Bantscheff, M. et al. Quantitative chemical proteomics reveals mechanisms of action of clinical ABL kinase inhibitors. Nature Biotech. 25, 1035-1044 (2007
153. Sliwkowski, M. X. & Mellman, I. Antibody therapeutics in cancer. Science 341, 1192-1198 (2013
154. Scott, A. M., Wolchok, J. D. & Old, L. J. Antibody therapy of cancer. Nature Rev. Cancer 12, 278-287 (2012
155. Verma, S. et al. Trastuzumab emtansine for HER2 positive advanced breast cancer. N. Engl. J. Med. 367, 1783-1791 (2012
156. Younes, A. et al. Results of a pivotal phase II study of brentuximab vedotin for patients with relapsed or refractory Hodgkin's lymphoma. J. Clin. Oncol. 30, 2183-2189 (2012
157. Chambers, C. A., Kuhns, M. S., Egen, J. G. & Allison, J. P. CTLA 4 mediated inhibition in regulation of T cell responses: Mechanisms and manipulation in tumor immunotherapy. Annu. Rev. Immunol. 19, 565-594 (2001
158. Topalian, S. L., Drake, C. G. & Pardoll, D. M. Targeting the PD 1/B7 H1(PD L1) pathway to activate anti-Tumor immunity. Curr. Opin. Immunol. 24, 207-212 (2012
159. Hodi, F. S. et al. Improved survival with ipilimumab in patients with metastatic melanoma. N. Engl. J. Med. 363, 711-723 (2010
160. Topalian, S. L. et al. Safety, activity, and immune correlates of anti PD 1 antibody in cancer. N. Engl. J. Med. 366, 2443-2454 (2012
161. Osborne, R. J. et al. Phase III trial of weekly methotrexate or pulsed dactinomycin for low-risk gestational trophoblastic neoplasia: A gynecologic oncology group study. J. Clin. Oncol. 29, 825-831 (2011
162. Bywater, M. J. et al. Inhibition of RNA polymerase I as a therapeutic strategy to promote cancer-specific activation of p53. Cancer Cell 22, 51-65 (2012
163. Lum, P. Y. et al. Discovering modes of action for therapeutic compounds using a genome-wide screen of yeast heterozygotes. Cell 116, 121-137 (2004
164. Rubbi, C. P. & Milner, J. Disruption of the nucleolus mediates stabilization of p53 in response to DNA damage and other stresses. EMBO J. 22, 6068-6077 (2003
165. Kurki, S. et al. Nucleolar protein NPM interacts with HDM2 and protects tumor suppressor protein p53 from HDM2 mediated degradation. Cancer Cell 5, 465-475 (2004
166. Sasaki, M. et al. Regulation of the MDM2 P53 pathway and tumor growth by PICT1 via nucleolar RPL11. Nature Med. 17, 944-951 (2011
167. Hein, N., Hannan, K. M., George, A. J., Sanij, E. & Hannan, R. D. The nucleolus: An emerging target for cancer therapy. Trends Mol. Med. 19, 643-654 (2013
168. Kaida, D. et al. Spliceostatin A targets SF3b and inhibits both splicing and nuclear retention of pre-mRNA. Nature Chem. Biol. 3, 576-583 (2007
169. Roybal, G. A. & Jurica, M. S. Spliceostatin A inhibits spliceosome assembly subsequent to prespliceosome formation. Nucleic Acids Res. 38, 6664-6672 (2010
170. Nakajima, H. et al. New antitumor substances, FR901463, FR901464 and FR901465. II. Activities against experimental tumors in mice and mechanism of action. J. Antibiot. 49, 1204-1211 (1996
171. Filipowicz, W., Bhattacharyya, S. N. & Sonenberg, N. Mechanisms of post-Transcriptional regulation by microRNAs: Are the answers in sight? Nature Rev. Genetics 9, 102-114 (2008
172. Calin, G. A. & Croce, C. M. MicroRNA-cancer connection: The beginning of a new tale. Cancer Res. 66, 7390-7394 (2006
173. Tan, G. S. et al. Small molecule inhibition of RISC loading. ACS Chem. Biol. 7, 403-410 (2012
174. Pare, J. M. et al. Hsp90 regulates the function of argonaute 2 and its recruitment to stress granules and P bodies. Mol. Biol. Cell 20, 3273-3284 (2009
175. Kumar, M. S. et al. Dicer1 functions as a haploinsufficient tumor suppressor. Genes Dev. 23, 2700-2704 (2009
176. Davis-Dusenbery, B. N. & Hata, A. MicroRNA in cancer: The involvement of aberrant microRNA biogenesis regulatory pathways. Genes Cancer 1, 1100-1114 (2010
177. Ruggero, D. & Pandolfi, P. P. Does the ribosome translate cancer? Nature Rev. Cancer 3, 179-192 (2003
178. Wetzler, M. & Segal, D. Omacetaxine as an anticancer therapeutic: What is old is new again. Curr. Pharm. Design 17, 59-64 (2011
179. Cortes, J. et al. Phase 2 study of subcutaneous omacetaxine mepesuccinate after TKI failure in patients with chronic-phase CML with T315I mutation. Blood 120, 2573-2580 (2012
180. Culjkovic-Kraljacic, B., Baguet, A., Volpon, L., Amri, A. & Borden, K. L. The oncogene eIF4E reprograms the nuclear pore complex to promote mRNA export and oncogenic transformation. Cell Rep. 2, 207-215 (2012
181. Kentsis, A., Topisirovic, I., Culjkovic, B., Shao, L. & Borden, K. L. Ribavirin suppresses eIF4E mediated oncogenic transformation by physical mimicry of the 7 methyl guanosine mRNA cap. Proc. Natl Acad. Sci. USA 101, 18105-18110 (2004
182. Assouline, S. et al. Molecular targeting of the oncogene eIF4E in acute myeloid leukemia (AML): A proof of principle clinical trial with ribavirin. Blood 114, 257-260 (2009
183. Pettersson, F. et al. Ribavirin treatment effects on breast cancers overexpressing eIF4E, a biomarker with prognostic specificity for luminal B type breast cancer. Clin. Cancer Res. 17, 2874-2884 (2011
184. Aloisi, A. et al. BCR-ABL nuclear entrapment kills human CML cells: Ex vivo study on 35 patients with the combination of imatinib mesylate and leptomycin B. Blood 107, 1591-1598 (2006
185. Azmi, A. S. et al. Selective inhibitors of nuclear export block pancreatic cancer cell proliferation and reduce tumor growth in mice. Gastroenterology 144, 447-456 (2012
186. Mutka, S. C. et al. Identification of nuclear export inhibitors with potent anticancer activity in vivo. Cancer Res. 69, 510-517 (2009
187. Etchin, J. et al. Antileukemic activity of nuclear export inhibitors that spare normal hematopoietic cells. Leukemia 27, 66-74 (2013
188. Vander Heiden, M. G., Cantley, L. C. & Thompson, C. B. Understanding the Warburg effect: The metabolic requirements of cell proliferation. Science 324, 1029-1033 (2009
189. Yang, W. et al. ERK1/2 dependent phosphorylation and nuclear translocation of PKM2 promotes the Warburg effect. Nature Cell Biol. 15, 124 (2012
190. Christofk, H. R., Vander Heiden, M. G., Wu, N., Asara, J. M. & Cantley, L. C. Pyruvate kinase M2 is a phosphotyrosine-binding protein. Nature 452, 181-186 (2008
191. Hitosugi, T. et al. Tyrosine phosphorylation inhibits PKM2 to promote the Warburg effect and tumor growth. Sci. Signal. 2, ra73 (2009
192. Schnabel, J. Targeting tumour metabolism. Nature Rev. Drug Discov. 9, 503-504 (2010
193. Teicher, B. A., Linehan, W. M. & Helman, L. J. Targeting cancer metabolism. Clin. Cancer Res. 18, 5537-5545 (2012
194. Colleoni, M. et al. Classical cyclophosphamide, methotrexate, and fluorouracil chemotherapy is more effective in triple-negative, node-negative breast cancer: Results from two randomized trials of adjuvant chemoendocrine therapy for node-negative breast cancer. J. Clin. Oncol. 28, 2966-2973 (2010
195. Wang, F. et al. Targeted inhibition of mutant IDH2 in leukemia cells induces cellular differentiation. Science 340, 622-626 (2013
196. Rohle, D. et al. An inhibitor of mutant IDH1 delays growth and promotes differentiation of glioma cells. Science 340, 626-630 (2013
197. Danial, N. N. et al. BAD and glucokinase reside in a mitochondrial complex that integrates glycolysis and apoptosis. Nature 424, 952-956 (2003
198. Raj, L. et al. Selective killing of cancer cells by a small molecule targeting the stress response to ROS. Nature 475, 231-234 (2011
199. Adams, D. J. et al. Synthesis, cellular evaluation, and mechanism of action of piperlongumine analogs. Proc. Natl Acad. Sci. USA 109, 15115-15120 (2012
200. Vaseva, A. V. et al. p53 opens the mitochondrial permeability transition pore to trigger necrosis. Cell 149, 1536-1548 (2012
201. Ni Chonghaile, T. & Letai, A. Mimicking the BH3 domain to kill cancer cells. Oncogene 27 (Suppl. 1), 149-157 (2008
202. Ni Chonghaile, T. et al. Pretreatment mitochondrial priming correlates with clinical response to cytotoxic chemotherapy. Science 334, 1129-1133 (2011
203. Ready, N. et al. Double-blind, placebo-controlled, randomized phase 2 study of the proapoptotic agent AT 101 plus docetaxel, in second-line non-small cell lung cancer. J. Thorac. Oncol. 6, 781-785 (2011
204. Sonpavde, G. et al. Randomized phase II trial of docetaxel plus prednisone in combination with placebo or AT 101, an oral small molecule Bcl 2 family antagonist, as first-line therapy for metastatic castration-resistant prostate cancer. Ann. Oncol. 23, 1803-1808 (2012
205. Kim, I., Xu, W. & Reed, J. C. Cell death and endoplasmic reticulum stress: Disease relevance and therapeutic opportunities. Nature Rev. Drug Discov. 7, 1013-1030 (2008
206. Denmeade, S. R. et al. Engineering a prostate-specific membrane antigen-Activated tumor endothelial cell prodrug for cancer therapy. Sci. Transl. Med. 4, 140ra186 (2012
207. Rubinsztein, D. C., Gestwicki, J. E., Murphy, L. O. & Klionsky, D. J. Potential therapeutic applications of autophagy. Nature Rev. Drug Discov. 6, 304-312 (2007
208. Janku, F., McConkey, D. J., Hong, D. S. & Kurzrock, R. Autophagy as a target for anticancer therapy. Nature Rev. Clin. Oncol. 8, 528-539 (2011
209. Kaufmann, A. M. & Krise, J. P. Lysosomal sequestration of amine-containing drugs: Analysis and therapeutic implications. J. Pharm. Sci. 96, 729-746 (2007
210. Goldberg, S. B. et al. A phase I study of erlotinib and hydroxychloroquine in advanced non-small-cell lung cancer. J. Thorac. Oncol. 7, 1602-1608 (2012
211. Saftig, P. & Sandhoff, K. Cancer: Killing from the inside. Nature 502, 312-313 (2013
212. Petersen, N. H. et al. Transformation-Associated changes in sphingolipid metabolism sensitize cells to lysosomal cell death induced by inhibitors of acid sphingomyelinase. Cancer Cell 24, 379-393 (2013
213. Belotti, D. et al. Paclitaxel (Taxol(R)) inhibits motility of paclitaxel-resistant human ovarian carcinoma cells. Clin. Cancer Res. 2, 1725-1730 (1996
214. Bonezzi, K. et al. Inhibition of SIRT2 potentiates the anti-motility activity of taxanes: Implications for antineoplastic combination therapies. Neoplasia 14, 846-854 (2012
215. Rotty, J. D., Wu, C. & Bear, J. E. New insights into the regulation and cellular functions of the ARP2/3 complex. Nature Rev. Mol. Cell Biol. 14, 7-12 (2013
216. Fernando, H. S., Kynaston, H. G. & Jiang, W. G. WASP and WAVE proteins: Vital intrinsic regulators of cell motility and their role in cancer (review). Int. J. Mol. Med. 23, 141-148 (2009
217. Teng, Y., Ngoka, L., Mei, Y., Lesoon, L. & Cowell, J. K. HSP90 and HSP70 proteins are essential for stabilization and activation of WASF3 metastasis-promoting protein. J. Biol. Chem. 287, 10051-10059 (2012
218. DeVita, V. T. Jr & Chu, E. A history of cancer chemotherapy. Cancer Res. 68, 8643-8653 (2008
219. Farber, S. & Diamond, L. K. Temporary remissions in acute leukemia in children produced by folic acid antagonist, 4 aminopteroyl-glutamic acid. N. Engl. J. Med. 238, 787-793 (1948
220. Li, M. C., Hertz, R. & Bergenstal, D. M. Therapy of choriocarcinoma and related trophoblastic tumors with folic acid and purine antagonists. N. Engl. J. Med. 259, 66-74 (1958
221. Johnson, I. S., Armstrong, J. G., Gorman, M. & Burnett, J. P. Jr. The vinca alkaloids: A new class of oncolytic agents. Cancer Res. 23, 1390-1427 (1963
222. Freireich, E. J., Karon, M. & Frei, E. I. Quadruple combination therapy (VAMP) for acute lymphocytic leukemia of childhood. Proc. Am. Assoc. Cancer Res. 5, 20 (1964
223. Wani, M. C., Taylor, H. L., Wall, M. E., Coggon, P. & McPhail, A. T. Plant antitumor agents. VI. The isolation and structure of taxol, a novel antileukemic and antitumor agent from Taxus brevifolia. J. Am. Chem. Soc. 93, 2325-2327 (1971
224. Wall, M. E. Camptothecin and taxol: Discovery to clinic. Med. Res. Rev. 18, 299-314 (1998
225. Druker, B. J. et al. Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nature Med. 2, 561-566 (1996
226. Roche-Lestienne, C. et al. Several types of mutations of the Abl gene can be found in chronic myeloid leukemia patients resistant to STI571, and they can pre-exist to the onset of treatment. Blood 100, 1014-1018 (2002
227. von Bubnoff, N., Schneller, F., Peschel, C. & Duyster, J. BCR-ABL gene mutations in relation to clinical resistance of Philadelphia-chromosome- positive leukaemia to STI571: A prospective study. Lancet 359, 487-491 (2002
228. Baselga, J. et al. Phase II study of weekly intravenous recombinant humanized anti p185HER2 monoclonal antibody in patients with HER2/neu-overexpressing metastatic breast cancer. J. Clin. Oncol. 14, 737-744 (1996
229. Davies, H. et al. Mutations of the BRAF gene in human cancer. Nature 417, 949-954 (2002
230. Yang, H. et al. RG7204 (PLX4032), a selective BRAFV600E inhibitor, displays potent antitumor activity in preclinical melanoma models. Cancer Res. 70, 5518-5527 (2010
231. Hoeflich, K. P. et al. Antitumor efficacy of the novel RAF inhibitor GDC 0879 is predicted by BRAFV600E mutational status and sustained extracellular signal-regulated kinase/mitogen-Activated protein kinase pathway suppression. Cancer Res. 69, 3042-3051 (2009
232. Flaherty, K. T. et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N. Engl. J. Med. 363, 809-819 (2010
233. Johannessen, C. M. et al. COT drives resistance to RAF inhibition through MAP kinase pathway reactivation. Nature 468, 968-972 (2010
234. Nazarian, R. et al. Melanomas acquire resistance to B RAF(V600E) inhibition by RTK or N RAS upregulation. Nature 468, 973-977 (2010
235. Yoshida, M., Kijima, M., Akita, M. & Beppu, T. Potent and specific inhibition of mammalian histone deacetylase both in vivo and in vitro by trichostatin A. J. Biol. Chem. 265, 17174-17179 (1990
236. Whitesell, L., Mimnaugh, E. G., De Costa, B., Myers, C. E. & Neckers, L. M. Inhibition of heat shock protein HSP90-pp60v src heteroprotein complex formation by benzoquinone ansamycins: Essential role for stress proteins in oncogenic transformation. Proc. Natl Acad. Sci. USA 91, 8324-8328 (1994
237. Rock, K. L. et al. Inhibitors of the proteasome block the degradation of most cell proteins and the generation of peptides presented on MHC class I molecules. Cell 78, 761-771 (1994
238. Butler, L. M. et al. Suberoylanilide hydroxamic acid, an inhibitor of histone deacetylase, suppresses the growth of prostate cancer cells in vitro and in vivo. Cancer Res. 60, 5165-5170 (2000
239. Weisberg, E., Manley, P. W., Cowan-Jacob, S. W., Hochhaus, A. & Griffin, J. D. Second generation inhibitors of BCR-ABL for the treatment of imatinib-resistant chronic myeloid leukaemia. Nature Rev. Cancer 7, 345-356 (2007
240. Baselga, J. & Swain, S. M. Novel anticancer targets: Revisiting ERBB2 and discovering ERBB3. Nature Rev. Cancer 9, 463-475 (2009
241. Stern, H. M. Improving treatment of HER2 positive cancers: Opportunities and challenges. Sci. Transl. Med. 4, 127rv122 (2012
242. Burris, H. A. Dual kinase inhibition in the treatment of breast cancer: Initial experience with the EGFR/ErbB 2 inhibitor lapatinib. Oncol. 9 (Suppl. 3), 10-15 (2004
243. Bollag, G. et al. Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma. Nature 467, 596-599 (2010
244. Poulikakos, P. I. et al. RAF inhibitor resistance is mediated by dimerization of aberrantly spliced BRAF(V600E). Nature 480, 387-390 (2011
245. Straussman, R. et al. Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion. Nature 487, 500-504 (2012
246. Villanueva, J. et al. Acquired resistance to BRAF inhibitors mediated by a RAF kinase switch in melanoma can be overcome by cotargeting MEK and IGF 1R/PI3K. Cancer Cell 18, 683-695 (2010
247. Metcalfe, C. & de Sauvage, F. J. Hedgehog fights back: Mechanisms of acquired resistance against Smoothened antagonists. Cancer Res. 71, 5057-5061 (2011
248. Von Hoff, D. D. et al. Inhibition of the hedgehog pathway in advanced basal-cell carcinoma. N. Engl. J. Med. 361, 1164-1172 (2009
249. Rudin, C. M. et al. Treatment of medulloblastoma with hedgehog pathway inhibitor GDC 0449. N. Engl. J. Med. 361, 1173-1178 (2009
250. Verstovsek, S. et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N. Engl. J. Med. 366, 799-807 (2012
251. Mesa, R. A., Yasothan, U. & Kirkpatrick, P. Ruxolitinib. Nature Rev. Drug Discov. 11, 103-104 (2012
252. Deshpande, A. et al. Kinase domain mutations confer resistance to novel inhibitors targeting JAK2V617F in myeloproliferative neoplasms. Leukemia 26, 708-715 (2012
253. Engelman, J. A. et al. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science 316, 1039-1043 (2007
254. Garofalo, M. et al. EGFR and MET receptor tyrosine kinase-Altered microRNA expression induces tumorigenesis and gefitinib resistance in lung cancers. Nature Med. 18, 74-82 (2012
255. Kobayashi, S. et al. EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N. Engl. J. Med. 352, 786-792 (2005
256. Bean, J. et al. MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib. Proc. Natl Acad. Sci. USA 104, 20932-20937 (2007
257. Wang, W. L. et al. Mechanisms of resistance to imatinib and sunitinib in gastrointestinal stromal tumor. Cancer Chemother. Pharmacol. 67 (Suppl. 1), 15-24 (2011
258. Gajiwala, K. S. et al. KIT kinase mutants show unique mechanisms of drug resistance to imatinib and sunitinib in gastrointestinal stromal tumor patients. Proc. Natl Acad. Sci. USA 106, 1542-1547 (2009
259. Villanueva, A. & Llovet, J. M. Second-line therapies in hepatocellular carcinoma: Emergence of resistance to sorafenib. Clin. Cancer Res. 18, 1824-1826 (2012
260. Chen, K. F. et al. Activation of phosphatidylinositol 3 kinase/Akt signaling pathway mediates acquired resistance to sorafenib in hepatocellular carcinoma cells. J. Pharmacol. Exp. Ther. 337, 155-161 (2011
261. Motzer, R. J. et al. Pazopanib versus sunitinib in metastatic renal-cell carcinoma. N. Engl. J. Med. 369, 722-731 (2013
262. Santoro, A. et al. Tivantinib for second-line treatment of advanced hepatocellular carcinoma: A randomised, placebo-controlled phase 2 study. Lancet Oncol. 14, 55-63 (2013
263. Baselga, J. et al. Phase II study of weekly intravenous trastuzumab (Herceptin) in patients with HER2/neu-overexpressing metastatic breast cancer. Seminars Oncol. 26, 78-83 (1999
264. Hudis, C. A. Trastuzumab-mechanism of action and use in clinical practice. N. Engl. J. Med. 357, 39-51 (2007
265. Katz, J., Janik, J. E. & Younes, A. Brentuximab vedotin (SGN 35). Clin. Cancer Res. 17, 6428-6436 (2011
266. Smith, M. R. Rituximab (monoclonal anti CD20 antibody): Mechanisms of action and resistance. Oncogene 22, 7359-7368 (2003
267. Bardelli, A. & Siena, S. Molecular mechanisms of resistance to cetuximab and panitumumab in colorectal cancer. J. Clin. Oncol. 28, 1254-1261 (2010
268. Montagut, C. et al. Identification of a mutation in the extracellular domain of the epidermal growth factor receptor conferring cetuximab resistance in colorectal cancer. Nature Med. 18, 221-223 (2012
269. Misale, S. et al. Emergence of KRAS mutations and acquired resistance to anti-EGFR therapy in colorectal cancer. Nature 486, 532-536 (2012
270. Loges, S., Schmidt, T. & Carmeliet, P. Mechanisms of resistance to anti-Angiogenic therapy and development of third-generation anti-Angiogenic drug candidates. Genes Cancer 1, 12-25 (2010
271. Holmgaard, R. B., Zamarin, D., Munn, D. H., Wolchok, J. D. & Allison, J. P. Indoleamine 2,3 dioxygenase is a critical resistance mechanism in antitumor T cell immunotherapy targeting CTLA 4. J. Exp. Med. 210, 1389-1402 (2013
272. Janne, P. A., Gray, N. & Settleman, J. Factors underlying sensitivity of cancers to small-molecule kinase inhibitors. Nature Rev. Drug Discov. 8, 709-723 (2009
273. Lopez-Contreras, A. J., Gutierrez-Martinez, P., Specks, J., Rodrigo-Perez, S. & Fernandez-Capetillo, O. An extra allele of Chk1 limits oncogene-induced replicative stress and promotes transformation. J. Exp. Med. 209, 455-461 (2012
274. Murga, M. et al. Exploiting oncogene-induced replicative stress for the selective killing of Myc-driven tumors. Nature Struct. Mol. Biol. 18, 1331-1335 (2011
275. Malumbres, M. Oncogene-induced mitotic stress: 53 and pRb get mad too. Cancer Cell 19, 691-692 (2011
276. Kops, G. J., Weaver, B. A. & Cleveland, D. W. On the road to cancer: Aneuploidy and the mitotic checkpoint. Nature Rev. Cancer 5, 773-785 (2005
277. Kaye, S. B. et al. Phase II, open-label, randomized, multicenter study comparing the efficacy and safety of olaparib, a poly (ADP-ribose) polymerase inhibitor, and pegylated liposomal doxorubicin in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer. J. Clin. Oncol. 30, 372-379 (2012
278. Plummer, R. et al. A phase II study of the potent PARP inhibitor, rucaparib (PF 01367338, AG014699), with temozolomide in patients with metastatic melanoma demonstrating evidence of chemopotentiation. Cancer Chemother. Pharmacol. 71, 1191-1199 (2013
279. Kummar, S. et al. A phase I study of veliparib in combination with metronomic cyclophosphamide in adults with refractory solid tumors and lymphomas. Clin. Cancer Res. 18, 1726-1734 (2012
280. Sulli, G., Di Micco, R. & d'Adda di Fagagna, F. Crosstalk between chromatin state and DNA damage response in cellular senescence and cancer. Nature Rev. Cancer 12, 709-720 (2012
281. Olsen, E. A. et al. Phase IIb multicenter trial of vorinostat in patients with persistent, progressive, or treatment refractory cutaneous T cell lymphoma. J. Clin. Oncol. 25, 3109-3115 (2007
282. Duvic, M. et al. Phase 2 trial of oral vorinostat (suberoylanilide hydroxamic acid, SAHA) for refractory cutaneous T cell lymphoma (CTCL). Blood 109, 31-39 (2007
283. Neri, P., Bahlis, N. J. & Lonial, S. Panobinostat for the treatment of multiple myeloma. Expert Opin. Investigat. Drugs 21, 733-747 (2012
284. Kaminskas, E., Farrell, A. T., Wang, Y. C., Sridhara, R. & Pazdur, R. FDA drug approval summary: Azacitidine (5 azacytidine, Vidaza™) for injectable suspension. Oncologist 10, 176-182 (2005
285. Lubbert, M. et al. Low-dose decitabine versus best supportive care in elderly patients with intermediate-or high-risk myelodysplastic syndrome (MDS) ineligible for intensive chemotherapy: Final results of the randomized phase III study of the European Organisation for Research and Treatment of Cancer Leukemia Group and the German MDS Study Group. J. Clin. Oncol. 29, 1987-1996 (2011
286. Kantarjian, H. M. et al. Multicenter, randomized, open-label, phase III trial of decitabine versus patient choice, with physician advice, of either supportive care or low-dose cytarabine for the treatment of older patients with newly diagnosed acute myeloid leukemia. J. Clin. Oncol. 30, 2670-2677 (2012
287. Morimoto, R. I. Proteotoxic stress and inducible chaperone networks in neurodegenerative disease and aging. Genes Dev. 22, 1427-1438 (2008
288. Socinski, M. A. et al. A multicenter Phase II study of ganetespib monotherapy in patients with genotypically defined advanced non-small cell lung cancer. Clin. Cancer Res. 19, 3068-3077 (2013
289. Eccles, S. A. et al. NVP AUY922: A novel heat shock protein 90 inhibitor active against xenograft tumor growth, angiogenesis, and metastasis. Cancer Res. 68, 2850-2860 (2008
290. Hrebackova, J., Hrabeta, J. & Eckschlager, T. Valproic acid in the complex therapy of malignant tumors. Curr. Drug Targets 11, 361-379 (2010
291. Duenas-Gonzalez, A. et al. Valproic acid as epigenetic cancer drug: Preclinical, clinical and transcriptional effects on solid tumors. Cancer Treatment Rev. 34, 206-222 (2008
292. Jagannath, S. et al. An open-label single-Arm pilot phase II study (PX 171 003 A0) of low-dose, single-Agent carfilzomib in patients with relapsed and refractory multiple myeloma. Clin. Lymphoma Myeloma Leuk. 12, 310-318 (2012
293. Siegel, D. S. et al. A phase 2 study of single-Agent carfilzomib (PX 171 003 A1) in patients with relapsed and refractory multiple myeloma. Blood 120, 2817-2825 (2012
294. Boulon, S., Westman, B. J., Hutten, S., Boisvert, F. M. & Lamond, A. I. The nucleolus under stress. Mol. Cell 40, 216-227 (2010
295. Derheimer, F. A. et al. RPA and ATR link transcriptional stress to p53. Proc. Natl Acad. Sci. USA 104, 12778-12783 (2007
296. Gilkes, D. M., Chen, L. & Chen, J. MDMX regulation of p53 response to ribosomal stress. EMBO J. 25, 5614-5625 (2006
297. Schonthal, A. H. Pharmacological targeting of endoplasmic reticulum stress signaling in cancer. Biochem. Pharmacol. 85, 653-666 (2013
298. Xu, C., Bailly-Maitre, B. & Reed, J. C. Endoplasmic reticulum stress: Cell life and death decisions. J. Clin. Invest. 115, 2656-2664 (2005
299. Thastrup, O., Cullen, P. J., Drobak, B. K., Hanley, M. R. & Dawson, A. P. Thapsigargin, a tumor promoter, discharges intracellular Ca2+ stores by specific inhibition of the endoplasmic reticulum Ca2+-ATPase. Proc. Natl Acad. Sci. USA 87, 2466-2470 (1990
300. Ganley, I. G., Wong, P. M., Gammoh, N. & Jiang, X. Distinct autophagosomal-lysosomal fusion mechanism revealed by thapsigargin-induced autophagy arrest. Mol. Cell 42, 731-743 (2011
301. Ohuchi, K. et al. Stimulation of arachidonic acid metabolism in rat peritoneal macrophages by thapsigargin, a non-(12 O tetradecanoylphorbol 13 acetate) (TPA)-Type tumor promoter. J. Cancer Res. Clin. Oncol. 113, 319-324 (1987
302. Wellen, K. E. & Thompson, C. B. Cellular metabolic stress: Considering how cells respond to nutrient excess. Mol. Cell 40, 323-332 (2010
303. Benz, C. C. & Yau, C. Ageing, oxidative stress and cancer: Paradigms in parallax. Nature Rev. Cancer 8, 875-879 (2008
304. Diaz, L. A. Jr. et al. The molecular evolution of acquired resistance to targeted EGFR blockade in colorectal cancers. Nature 486, 537-540 (2012
305. Wilson, T. R. et al. Widespread potential for growth-factor-driven resistance to anticancer kinase inhibitors. Nature 487, 505-509 (2012