Preclinical development of molecular-targeted agents for cancer

Nature Reviews Clinical Oncology

Volumn 8, Issue 4, 2011, Pages 200-209

  Ocana, Alberto ^a   Pandiella, Atanasio ^b   Siu, Lillian L ^c   Tannock, Ian F ^c  

^a HOSPITAL GENERAL UNIVERSITARIO DE ALBACETE   (Spain)

^b CSIC   (Spain)

^c UNIVERSITY OF TORONTO   (Canada)

Author keywords

[No Author keywords available]

Indexed keywords

AFATINIB; BCR ABL PROTEIN; BRCA1 PROTEIN; BRCA2 PROTEIN; CANERTINIB; CETUXIMAB; DASATINIB; EPIDERMAL GROWTH FACTOR RECEPTOR; EPIDERMAL GROWTH FACTOR RECEPTOR 2; EPIDERMAL GROWTH FACTOR RECEPTOR KINASE INHIBITOR; ERLOTINIB; EVEROLIMUS; GEFITINIB; IMATINIB; K RAS PROTEIN; LAPATINIB; MAMMALIAN TARGET OF RAPAMYCIN INHIBITOR; MITOGEN ACTIVATED PROTEIN KINASE INHIBITOR; NERATINIB; NICOTINAMIDE ADENINE DINUCLEOTIDE ADENOSINE DIPHOSPHATE RIBOSYLTRANSFERASE INHIBITOR; OLAPARIB; PERTUZUMAB; PHOSPHATIDYLINOSITOL 3 KINASE; PHOSPHATIDYLINOSITOL 3 KINASE INHIBITOR; PROTEIN INHIBITOR; PROTEIN P110; SMALL INTERFERING RNA; TRASTUZUMAB;

ANTINEOPLASTIC ACTIVITY; BIOLOGICAL MODEL; BREAST CANCER; CANCER CELL CULTURE; CANCER COMBINATION CHEMOTHERAPY; CANCER MODEL; CANCER PREVENTION; CANCER RESEARCH; CANCER RESISTANCE; CHRONIC MYELOID LEUKEMIA; COLON ADENOMA; COLON CANCER; DRUG EFFECT; DRUG EFFICACY; DRUG POTENCY; DRUG SCREENING; EX VIVO STUDY; GENE EXPRESSION PROFILING; GENE MUTATION; GENE OVEREXPRESSION; GENETIC ASSOCIATION; GENETIC ENGINEERING; HEAD AND NECK CANCER; HUMAN; LUNG CANCER; MOLECULARLY TARGETED THERAPY; NONHUMAN; OVARY CANCER; PRIORITY JOURNAL; PROSTATE CANCER; REVIEW; TREATMENT PLANNING; TUMOR XENOGRAFT;

ANIMALS; ANTINEOPLASTIC AGENTS; DRUG EVALUATION, PRECLINICAL; HUMANS; MICE; NEOPLASM PROTEINS; NEOPLASMS;

EID: 79953244384     PISSN: 17594774     EISSN: 17594782     Source Type: Journal    
DOI: 10.1038/nrclinonc.2010.194     Document Type: Review

References (120)

1. DiMasi, J. A. & Grabowski, H. G. Economics of new oncology drug development. J. Clin. Oncol. 25, 209-216 (2007). (Pubitemid 350003036)
2. Kola, I. & Landis, J. Can the pharmaceutical industry reduce attrition rates? Nat. Rev. Drug Discov. 3, 711-715 (2004). (Pubitemid 39173511)
3. Sawyers, C. L. Translational research: are we on the right track? 2008 American Society for Clinical Investigation Presidential Address. J. Clin. Invest. 118, 3798-3801 (2008).
4. Sharpless, N. E. & Depinho, R. A. The mighty mouse: genetically engineered mouse models in cancer drug development. Nat. Rev. Drug Discov. 5, 741-754 (2006). (Pubitemid 44323701)
5. Rubinstein, L. V. et al. Comparison of in vitro anticancer-drug-screening data generated with a tetrazolium assay versus a protein assay against a diverse panel of human tumor cell lines. J. Natl Cancer Inst. 82, 1113-1118 (1990). (Pubitemid 20213251)
6. Szacáks, G. & Gottesman, M. Comparing solid tumors with cell lines: implications for identifying drug resistance genes in cancer. Mol. Interv. 4, 323-325 (2004). (Pubitemid 40124379)
7. Sharma, S. V., Haber, D. A. & Settleman, J. Cell line-based platforms to evaluate the therapeutic efficacy of candidate anticancer agents. Nat. Rev. Cancer 10, 241-253 (2010).
8. Deininger, M. W., Goldman, J. M., Lydon, N. & Melo, J. V. The tyrosine kinase inhibitor CGP57148B selectively inhibits the growth of BCR-ABL-positive cells. Blood 90, 3691-3698 (1997). (Pubitemid 27473440)
9. Garayoa, M. et al. Mesenchymal stem cells from multiple myeloma patients display distinct genomic profile as compared with those from normal donors. Leukemia 23, 1515-1527 (2009).
10. Azab, A. K. et al. CXCR4 inhibitor AMD3100 disrupts the interaction of multiple myeloma cells with the bone marrow microenvironment and enhances their sensitivity to therapy. Blood 113, 4341-4351 (2009).
11. McMillin, D. W. et al. Antimyeloma activity of the orally bioavailable dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor NVP-BEZ235. Cancer Res. 69, 5835-5842 (2009).
12. Ocio, E. M. et al. Zalypsis: a novel marine-derived compound with potent antimyeloma activity that reveals high sensitivity of malignant plasma cells to DNA double-strand breaks. Blood 113, 3781-3791 (2009).
13. Mitsiades, C. S. et al. Aplidin, a marine organism-derived compound with potent antimyeloma activity in vitro and in vivo. Cancer Res. 68, 5216-5225 (2008).
14. Ocaña, A., Hortobagyi, G. N. & Esteva, F. J. Concomitant versus sequential chemotherapy in the treatment of early-stage and metastatic breast cancer. Clin. Breast Cancer 6, 495-504 (2006).
15. Chou, T. C. Theoretical basis, experimental design, and computerized simulation of synergism and antagonism in drug combination studies. Pharmacol. Rev. 58, 621-681 (2006).
16. Minchinton, A. I. & Tannock, I. F. Drug penetration in solid tumours. Nat. Rev. Cancer 6, 583-592 (2006). (Pubitemid 44140857)
17. Polyak, K., Haviv, I. & Campbell, I. G. Co-evolution of tumor cells and their microenvironment. Trends Genet. 25, 30-38 (2009).
18. Visvader, J. E. & Lindeman, G. J. Cancer stem cells in solid tumours: accumulating evidence and unresolved questions. Nat. Rev. Cancer 8, 755-768 (2008).
19. Korkaya, H., Paulson, A., Iovino, F. & Wicha, M. S. HER2 regulates the mammary stem/progenitor cell population driving tumorigenesis and invasion. Oncogene 27, 6120-6130 (2008).
20. Dubrovska, A. et al. The role of PTEN/Akt/PI3K signaling in the maintenance and viability of prostate cancer stem-like cell populations. Proc. Natl Acad. Sci. USA 106, 268-273 (2009).
21. Al-Hajj, M., Wicha, M. S., Benito-Hernandez, A., Morrison, S. J. & Clarke, M. F. Prospective identification of tumorigenic breast cancer cells. Proc. Natl Acad. Sci. USA 100, 3983-3988 (2003). (Pubitemid 36418143)
22. Ponti, D. et al. Isolation and in vitro propagation of tumorigenic breast cancer cells with stem/progenitor cell properties. Cancer Res. 65, 5506-5511 (2005). (Pubitemid 40911148)
23. Vlashi, E. et al. In vivo imaging, tracking, and targeting of cancer stem cells. J. Natl Cancer Inst. 101, 350-359 (2009).
24. Dean, M., Fojo, T. & Bates, S. Tumour stem cells and drug resistance. Nat. Rev. Cancer 5, 275-284 (2005). (Pubitemid 40488633)
25. Gupta, P. B. et al. Identification of selective inhibitors of cancer stem cells by high-throughput screening. Cell 138, 645-659 (2009).
26. Dreher, M. R. et al. Tumor vascular permeability, accumulation, and penetration of macromolecular drug carriers. J. Natl Cancer Inst. 98, 335-344 (2006). (Pubitemid 43338213)
27. Primeau, A. J., Rendon, A., Hedley, D., Lilge, L. & Tannock, I. F. The distribution of the anticancer drug doxorubicin in relation to blood vessels in solid tumors. Clin. Cancer Res. 11, 8782-8788 (2005). (Pubitemid 43005929)
28. Huxham, L. A., Kyle, A. H., Baker, J. H., Nykilchuk, L. K. & Minchinton, A. I. Microregional effects of gemcitabine in HCT-116 xenografts. Cancer Res. 64, 6537-6541 (2004). (Pubitemid 39297911)
29. Casciari, J. J. et al. Growth and chemotherapeutic response of cells in a hollow-fiber in vitro solid tumor model. J. Natl Cancer Inst. 86, 1846-1852 (1994).
30. Decker, S., Hollingshead, M., Bonomi, C. A., Carter, J. P. & Sausville, E. A. The hollow fibre model in cancer drug screening: the NCI experience. Eur. J. Cancer 40, 821-826 (2004). (Pubitemid 38519760)
31. Johnson, J. I. et al. Relationships between drug activity in NCI preclinical in vitro and in vivo models and early clinical trials. Br. J. Cancer 84, 1424-1431 (2001). (Pubitemid 32522115)
32. Teicher, B. A. Tumor models for efficacy determination. Mol. Cancer Ther. 5, 2435-2443 (2006). (Pubitemid 44650906)
33. Weissleder, R. Scaling down imaging: molecular mapping of cancer in mice. Nat. Rev. Cancer 2, 11-18 (2002). (Pubitemid 37328803)
34. Olive, K. P. & Tuveson, D. A. The use of targeted mouse models for preclinical testing of novel cancer therapeutics. Clin. Cancer Res. 12, 5277-5287 (2006). (Pubitemid 44497240)
35. Graves, E. E., Weissleder, R. & Ntziachristos, V. Fluorescence molecular imaging of small animal tumor models. Curr. Mol. Med. 4, 419-430 (2004). (Pubitemid 38787010)
36. Carver, B. S. & Pandolfi, P. P. Mouse modeling in oncologic preclinical and translational research. Clin. Cancer Res. 12, 5305-5311 (2006). (Pubitemid 44497243)
37. Bibby, M. C. Orthotopic models of cancer for preclinical drug evaluation: advantages and disadvantages. Eur. J. Cancer 40, 852-857 (2004). (Pubitemid 38519764)
38. Nakamura, T., Fidler, I. J. & Coombes, K. R. Gene expression profile of metastatic human pancreatic cancer cells depends on the organ microenvironment. Cancer Res. 67, 139-148 (2007). (Pubitemid 46142769)
39. Rangarajan, A. & Weinberg, R. A. Opinion: Comparative biology of mouse versus human cells: modelling human cancer in mice. Nat. Rev. Cancer 3, 952-959 (2003). (Pubitemid 37500180)
40. Van Dyke, T. & Jacks, T. Cancer modeling in the modern era: progress and challenges. Cell 108, 135-144 (2002). (Pubitemid 34161134)
41. Balmain, A. Cancer as a complex genetic trait: tumor susceptibility in humans and mouse models. Cell 108, 145-152 (2002). (Pubitemid 34161135)
42. Stewart, T. A., Bellve, A. R. & Leder, P. Transcription and promoter usage of the myc gene in normal somatic and spermatogenic cells. Science 226, 707-710 (1984). (Pubitemid 15202153)
43. Quaife, C. J., Pinkert, C. A., Ornitz, D. M., Palmiter, R. D. & Brinster, R. L. Pancreatic neoplasia induced by ras expression in acinar cells of transgenic mice. Cell 48, 1023-1034 (1987).
44. 53 in mice induces mammary tumors with features of human BRCA1-mutated basal-like breast cancer. Proc. Natl Acad. Sci. USA 104, 12111-12116 (2007). (Pubitemid 47185638)
45. Rottenberg, S. et al. High sensitivity of BRCA1-deficient mammary tumors to the PARP inhibitor AZD2281 alone and in combination with platinum drugs. Proc. Natl Acad. Sci. USA 105, 17079-17084 (2008).
46. Politi, K. et al. Lung adenocarcinomas induced in mice by mutant EGF receptors found in human lung cancers respond to a tyrosine kinase inhibitor or to down-regulation of the receptors. Genes Dev. 20, 1496-1510 (2006). (Pubitemid 43830656)
47. Ji, H. et al. The impact of human EGFR kinase domain mutations on lung tumorigenesis and in vivo sensitivity to EGFR-targeted therapies. Cancer Cell 9, 485-495 (2006). (Pubitemid 43832191)
48. Casanovas, O., Hicklin, D. J., Bergers, G. & Hanahan, D. Drug resistance by evasion of antiangiogenic targeting of VEGF signaling in late-stage pancreatic islet tumors. Cancer Cell 8, 299-309 (2005). (Pubitemid 41443415)
49. Strecker, T. E. et al. Effect of lapatinib on the development of estrogen receptor-negative mammary tumors in mice. J. Natl Cancer Inst. 101, 107-113 (2009).
50. Fujishita, T., Aoki, K., Lane, H. A., Aoki, M. & Taketo, M. M. Inhibition of the mTORC1 pathway suppresses intestinal polyp formation and reduces mortality in ApcDelta716 mice. Proc. Natl Acad. Sci. USA 105, 13544-13549 (2008).
51. Orban, P. C., Chui, D. & Marth, J. D. Tissue- and site-specific DNA recombination in transgenic mice. Proc. Natl Acad. Sci. USA 89, 6861-6865 (1992).
52. Sauer, B. & McDermott, J. DNA recombination with a heterospecific Cre homolog identified from comparison of the pac-c1 regions of P1-related phages. Nucleic Acids Res. 32, 6086-6095 (2004). (Pubitemid 40074003)
53. Indra, A. K. et al. Temporally-controlled site-specific mutagenesis in the basal layer of the epidermis: comparison of the recombinase activity of the tamoxifen-inducible Cre-ER(T) and Cre-ER(T2) recombinases. Nucleic Acids Res. 27, 4324-4327 (1999). (Pubitemid 29533170)
54. Kistner, A. et al. Doxycycline-mediated quantitative and tissue-specific control of gene expression in transgenic mice. Proc. Natl Acad. Sci. USA 93, 10933-10938 (1996). (Pubitemid 26333095)
55. Rottenberg, S. et al. Selective induction of chemotherapy resistance of mammary tumors in a conditional mouse model for hereditary breast cancer. Proc. Natl Acad. Sci. USA 104, 12117-12122 (2007). (Pubitemid 47185639)
56. Gillies, R. J. et al. Applications of magnetic resonance in model systems: tumor biology and physiology. Neoplasia 2, 139-151 (2000). (Pubitemid 30123185)
57. Bradley, D. P. et al. Examining the acute effects of cediranib (RECENTIN, AZD2171) treatment in tumor models: a dynamic contrast-enhanced MRI study using gadopentate. Magn. Reson. Imaging 27, 377-384 (2009).
58. Morgan, B. et al. Dynamic contrast-enhanced magnetic resonance imaging as a biomarker for the pharmacological response of PTK787/ZK 222584, an inhibitor of the vascular endothelial growth factor receptor tyrosine kinases, in patients with advanced colorectal cancer and liver metastases: results from two phase I studies. J. Clin. Oncol. 21, 3955-3964 (2003). (Pubitemid 46606209)
59. Kennel, S. J. et al. High resolution computed tomography and MRI for monitoring lung tumor growth in mice undergoing radioimmunotherapy: correlation with histology. Med. Phys. 27, 1101-1107 (2000). (Pubitemid 30350021)
60. Rooks, V., Beecken, W. D., Iordanescu, I. & Taylor, G. A. Sonographic evaluation of orthotopic bladder tumors in mice treated with TNP-470, an angiogenic inhibitor. Acad. Radiol. 8, 121-127 (2001). (Pubitemid 32666470)
61. Drevs, J. et al. Effects of PTK787/ZK 222584, a specific inhibitor of vascular endothelial growth factor receptor tyrosine kinases, on primary tumor, metastasis, vessel density, and blood flow in a murine renal cell carcinoma model. Cancer Res. 60, 4819-4824 (2000).
62. Zhang, X. H. et al. Latent bone metastasis in breast cancer tied to Src-dependent survival signals. Cancer Cell 16, 67-78 (2009).
63. Gupta, G. P. et al. Mediators of vascular remodelling co-opted for sequential steps in lung metastasis. Nature 446, 765-770 (2007). (Pubitemid 46582040)
64. Bos, P. D. et al. Genes that mediate breast cancer metastasis to the brain. Nature 459, 1005-1009 (2009).
65. Mendel, D. B. et al. In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: determination of a pharmacokinetic/pharmacodynamic relationship. Clin. Cancer Res. 9, 327-337 (2003). (Pubitemid 36109749)
66. Zalutsky, M. R. et al. Radioiodinated antibody targeting of the HER-2/neu oncoprotein: effects of labeling method on cellular processing and tissue distribution. Nucl. Med. Biol. 26, 781-790 (1999). (Pubitemid 29509802)
67. Austin, C. D. et al. Endocytosis and sorting of ErbB2 and the site of action of cancer therapeutics trastuzumab and geldanamycin. Mol. Biol. Cell 15, 5268-5282 (2004). (Pubitemid 39564723)
68. Iorns, E., Lord, C. J., Turner, N. & Ashworth, A. Utilizing RNA interference to enhance cancer drug discovery. Nat. Rev. Drug Discov. 6, 556-568 (2007). (Pubitemid 47019444)
69. Shaffer, A. L. et al. IRF4 addiction in multiple myeloma. Nature 454, 226-231 (2008). (Pubitemid 351969894)
70. Turner, N. C. et al. A synthetic lethal siRNA screen identifying genes mediating sensitivity to a PARP inhibitor. EMBO J. 27, 1368-1377 (2008). (Pubitemid 351655175)
71. Iorns, E. et al. Integrated functional, gene expression and genomic analysis for the identification of cancer targets. PLoS ONE 4, e5120 (2009).
72. Swanton, C. et al. Regulators of mitotic arrest and ceramide metabolism are determinants of sensitivity to paclitaxel and other chemotherapeutic drugs. Cancer Cell 11, 498-512 (2007). (Pubitemid 46856907)
73. Iorns, E. et al. Identification of CDK10 as an important determinant of resistance to endocrine therapy for breast cancer. Cancer Cell 13, 91-104 (2008). (Pubitemid 351163160)
74. 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). (Pubitemid 47539306)
75. Goulart, B. H. et al. Trends in the use and role of biomarkers in phase I oncology trials. Clin. Cancer Res. 13, 6719-6726 (2007). (Pubitemid 350206809)
76. Shah, N. P. et al. Intermittent target inhibition with dasatinib 100 mg once daily preserves efficacy and improves tolerability in imatinib-resistant and -intolerant chronic-phase chronic myeloid leukemia. J. Clin. Oncol. 26, 3204-3212 (2008).
77. Shah, N. P. et al. Transient potent BCR-ABL inhibition is sufficient to commit chronic myeloid leukemia cells irreversibly to apoptosis. Cancer Cell 14, 485-493 (2008).
78. Oda, T. et al. Crkl is the major tyrosine-phosphorylated protein in neutrophils from patients with chronic myelogenous leukemia.J. Biol. Chem. 269, 22925-22928 (1994). (Pubitemid 24283264)
79. Tanaka, C. et al. Identifying optimal biologic doses of everolimus (RAD001) in patients with cancer based on the modeling of preclinical and clinical pharmacokinetic and pharmacodynamic data. J. Clin. Oncol. 26, 1596-1602 (2008).
80. Ritter, C. A. et al. Human breast cancer cells selected for resistance to trastuzumab in vivo overexpress epidermal growth factor receptor and ErbB ligands and remain dependent on the ErbB receptor network. Clin. Cancer Res. 13, 4909-4919 (2007). (Pubitemid 47294799)
81. Ayers, M., Fargnoli, J., Lewin, A., Wu, Q. & Platero, J. S. Discovery and validation of biomarkers that respond to treatment with brivanib alaninate, a small-molecule VEGFR-2/FGFR-1 antagonist. Cancer Res. 67, 6899-6906 (2007). (Pubitemid 47105537)
82. Crone, S. A. et al. ErbB2 is essential in the prevention of dilated cardiomyopathy. Nat. Med. 8, 459-465 (2002). (Pubitemid 34546747)
83. Threadgill, D. W. et al. Targeted disruption of mouse EGF receptor: effect of genetic background on mutant phenotype. Science 269, 230-234 (1995).
84. Ocana, A., Serrano, R., Calero, R. & Pandiella, A. Novel tyrosine kinase inhibitors in the treatment of cancer. Curr. Drug Targets 10, 575-576 (2009).
85. Yun, C. H. et al. The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP. Proc. Natl Acad. Sci. USA 105, 2070-2075 (2008).
86. Talpaz, M. et al. Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. N. Engl. J. Med. 354, 2531-2541 (2006). (Pubitemid 43882349)
87. Li, D. et al. BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models. Oncogene 27, 4702-4711 (2008).
88. Minami, Y. et al. The major lung cancer-derived mutants of ERBB2 are oncogenic and are associated with sensitivity to the irreversible EGFR/ERBB2 inhibitor HKI-272. Oncogene 26, 5023-5027 (2007). (Pubitemid 47172642)
89. Engelman, J. A. et al. PF00299804, an irreversible pan-ERBB inhibitor, is effective in lung cancer models with EGFR and ERBB2 mutations that are resistant to gefitinib. Cancer Res. 67, 11924-11932 (2007).
90. Jabbour, E. et al. Frequency and clinical significance of BCR-ABL mutations in patients with chronic myeloid leukemia treated with imatinib mesylate. Leukemia 20, 1767-1773 (2006). (Pubitemid 44574988)
91. Shah, N. P. et al. Overriding imatinib resistance with a novel ABL kinase inhibitor. Science 305, 399-401 (2004). (Pubitemid 38938156)
92. Kantarjian, H. et al. Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL. N. Engl. J. Med. 354, 2542-2551 (2006). (Pubitemid 43882350)
93. Kwak, E. L. et al. Irreversible inhibitors of the EGF receptor may circumvent acquired resistance to gefitinib. Proc. Natl Acad. Sci. USA 102, 7665-7670 (2005). (Pubitemid 40741028)
94. Li, D. et al. Bronchial and peripheral murine lung carcinomas induced by T790M-L858R mutant EGFR respond to HKI-272 and rapamycin combination therapy. Cancer Cell 12, 81-93 (2007). (Pubitemid 47001787)
95. Ocaña, A. & Amir, E. Irreversible pan-ErbB tyrosine kinase inhibitors and breast cancer: current status and future directions. Cancer Treat. Rev. 3, 685-691 (2009).
96. Burstein, H. et al. Neratinib (HKI-272), an irreversible pan erbB receptor tyrosine kinase inhibitor: phase 2 results in patients with advanced HER2+ breast cancer [abstract]. Cancer Res. 69 (Suppl.), a37 (2008).
97. Ocana, A., Amir, E., Seruga, B. & Pandiella, A. Do we have to change the way targeted drugs are developed? J. Clin. Oncol. 28, 420-421 (2010).
98. Engelman, J. A. et al. Effective use of PI3K and MEK inhibitors to treat mutant Kras G12D and PIK3CA H1047R murine lung cancers. Nat. Med. 14, 1351-1356 (2008).
99. Faber, A. C. et al. Differential induction of apoptosis in HER2 and EGFR addicted cancers following PI3K inhibition. Proc. Natl Acad. Sci. USA 106, 19503-19508 (2009).
100. Kaelin, W. G. Jr. The concept of synthetic lethality in the context of anticancer therapy. Nat. Rev. Cancer 5, 689-698 (2005). (Pubitemid 41486362)
101. Turner, N., Tutt, A. & Ashworth, A. Hallmarks of 'BRCAness' in sporadic cancers. Nat. Rev. Cancer 4, 814-819 (2004). (Pubitemid 39331153)
102. Iglehart, J. D. & Silver, D. P. Synthetic lethality-a new direction in cancer-drug development. N. Engl. J. Med. 361, 189-191 (2009).
103. Garber, J. E. et al. Neo-adjuvant cisplatin (CDDP) in triple-negative breast cancer (BC) [abstract]. Breast Cancer Res. Treat. 100 (Suppl. 1), a3074 (2006).
104. O'Shaughnessy, J. et al. Efficacy of BSI-201, a poly (ADP-ribose) polymerase-1 (PARP1) inhibitor, in combination with gemcitabine/carboplatin (G/C) in patients with metastatic triple-negative breast cancer (TNBC): results of a randomized phase II trial [abstract]. J. Clin. Oncol. 27 (18 Suppl.), a3 (2009).
105. Fong, P. C. et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N. Engl. J. Med. 361, 123-134 (2009).
106. Sliwkowski, M. X. et al. Nonclinical studies addressing the mechanism of action of trastuzumab (Herceptin). Semin. Oncol. 26, 60-70 (1999). (Pubitemid 29411434)
107. Gelmon, K. A. et al. Results of a phase II trial of trastuzumab (H) and pertuzumab (P) in patients (pts) with HER2-positive metastatic breast cancer (MBC) who had progressed during trastuzumab therapy [abstract]. J. Clin. Oncol. 26 (Suppl.), a1026 (2008).
108. Craft, N., Shostak, Y., Carey, M. & Sawyers, C. L. A mechanism for hormone-independent prostate cancer through modulation of androgen receptor signaling by the HER-2/neu tyrosine kinase. Nat. Med. 5, 280-285 (1999). (Pubitemid 29124362)
109. Raben, D. et al. The effects of cetuximab alone and in combination with radiation and/or chemotherapy in lung cancer. Clin. Cancer Res. 11, 795-805 (2005). (Pubitemid 40116908)
110. Huang, S. M. & Harari, P. M. Modulation of radiation response after epidermal growth factor receptor blockade in squamous cell carcinomas: inhibition of damage repair, cell cycle kinetics, and tumor angiogenesis. Clin. Cancer Res. 6, 2166-2174 (2000). (Pubitemid 30399181)
111. Ciardiello, F. et al. Antitumor activity of sequential treatment with topotecan and anti-epidermal growth factor receptor monoclonal antibody C225. Clin. Cancer Res. 5, 909-916 (1999). (Pubitemid 29180844)
112. Greulich, H. et al. Oncogenic transformation by inhibitor-sensitive and -resistant EGFR mutants. PLoS Med. 2, e313 (2005).
113. Ng, S. S., Tsao, M. S., Nicklee, T. & Hedley, D. W. Effects of the epidermal growth factor receptor inhibitor OSI-774, Tarceva, on downstream signaling pathways and apoptosis in human pancreatic adenocarcinoma. Mol. Cancer Ther. 1, 777-783 (2002).
114. Scaltriti, M. et al. Expression of p95HER2, a truncated form of the HER2 receptor, and response to anti-HER2 therapies in breast cancer. J. Natl Cancer Inst. 99, 628-638 (2007). (Pubitemid 47073544)
115. Rabindran, S. K. et al. Antitumor activity of HKI-272, an orally active, irreversible inhibitor of the HER-2 tyrosine kinase. Cancer Res. 64, 3958-3965 (2004). (Pubitemid 38697310)
116. Dudkin, L. et al. Biochemical correlates of mTOR inhibition by the rapamycin ester CCI-779 and tumor growth inhibition. Clin. Cancer Res. 7, 1758-1764 (2001). (Pubitemid 32708646)
117. She, Q. B. et al. Breast tumor cells with PI3K mutation or HER2 amplification are selectively addicted to Akt signaling. PLoS ONE 3, e3065 (2008).
118. 53;-mutant mammary tumors in vivo and delays tumor relapse in combination with carboplatin. Cancer Res. 69, 3850-3855 (2009).
119. Hu, Y. et al. Targeting multiple kinase pathways in leukemic progenitors and stem cells is essential for improved treatment of Ph+ leukemia in mice. Proc. Natl Acad. Sci. USA 103, 16870-16875 (2006). (Pubitemid 44737345)
120. Guix, M. et al. Acquired resistance to EGFR tyrosine kinase inhibitors in cancer cells is mediated by loss of IGF-binding proteins. J. Clin. Invest. 118, 2609-2619 (2008). (Pubitemid 351949788)