That which does not kill me makes me stronger; Combining ERK1/2 pathway inhibitors and BH3 mimetics to kill tumour cells and prevent acquired resistance

British Journal of Pharmacology

Volumn 169, Issue 8, 2013, Pages 1708-1722

  Sale, Matthew J ^a   Cook, Simon J ^a  

^a BABRAHAM INSTITUTE   (United Kingdom)

Author keywords

acquired resistance; apoptosis; BCL2; BRAF; cancer; ERK1 2; MEK1 2; RAS; targeted therapeutics

Indexed keywords

4 [4 (4' CHLORO 2 BIPHENYLYLMETHYL) 1 PIPERAZINYL] N [4 [3 DIMETHYLAMINO 1 (PHENYLTHIOMETHYL)PROPYLAMINO] 3 NITROBENZENESULFONYL]BENZAMIDE; B RAF KINASE; B RAF KINASE INHIBITOR; BH3 PROTEIN; BIM PROTEIN; G 963; MITOGEN ACTIVATED PROTEIN KINASE 1; MITOGEN ACTIVATED PROTEIN KINASE 3; MITOGEN ACTIVATED PROTEIN KINASE INHIBITOR; N [3 (5 CHLORO 1H PYRROLO[2,3 B]PYRIDINE 3 CARBONYL) 2,4 DIFLUOROPHENYL]PROPANESULFONAMIDE; NAVITOCLAX; OBATOCLAX; PICTILISIB; PROTEIN BCL 2; PROTEIN BCL X; PROTEIN MCL 1; SELUMETINIB; TOPOTECAN; UNCLASSIFIED DRUG;

APOPTOSIS; CANCER COMBINATION CHEMOTHERAPY; CANCER RESISTANCE; CELL SURVIVAL; CHEMOSENSITIVITY; CHRONIC LYMPHATIC LEUKEMIA; CYTOSTASIS; DRUG BIOAVAILABILITY; DRUG CYTOTOXICITY; DRUG DISTRIBUTION; DRUG EFFICACY; DRUG MECHANISM; DRUG POTENTIATION; ENZYME INHIBITION; HUMAN; LUNG SMALL CELL CANCER; MONOTHERAPY; NONHUMAN; ONCOGENE K RAS; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN FAMILY; PROTEIN FUNCTION; PROTEIN PHOSPHORYLATION; PROTEIN PROTEIN INTERACTION; REGULATORY MECHANISM; REVIEW;

ACQUIRED RESISTANCE; APOPTOSIS; BCL2; BRAF; CANCER; ERK1/2; MEK1/2; RAS; TARGETED THERAPEUTICS;

ANILINE COMPOUNDS; ANIMALS; ANTINEOPLASTIC COMBINED CHEMOTHERAPY PROTOCOLS; APOPTOSIS; APOPTOSIS REGULATORY PROTEINS; BENZAMIDES; CELL CYCLE; CELL LINE, TUMOR; DOWN-REGULATION; DRUG RESISTANCE, NEOPLASM; HUMANS; INDOLES; MAP KINASE KINASE 1; MAP KINASE SIGNALING SYSTEM; MITOGEN-ACTIVATED PROTEIN KINASE 3; MOLECULAR TARGETED THERAPY; NEOPLASMS; PIPERAZINES; PROTO-ONCOGENE PROTEINS B-RAF; PYRIMIDINES; SULFONAMIDES;

EID: 84881326118     PISSN: 00071188     EISSN: 14765381     Source Type: Journal    
DOI: 10.1111/bph.12220     Document Type: Review

References (147)

1. Andrews M, Behren A, Chiohn F, Tebbutt N, Do H, Dobrovic A, et al. (2012). Colorectal cancer promoted in a melanoma patient receiving dabrafenib (GSK2118436) in combination with MEK1/2 inhibitor trametinib (GSK1120212). Pigment Cell Melanoma Res 25: 842.
2. Anforth RM, Blumetti TC, Kefford RF, Sharma R, Scolyer RA, Kossard S, et al. (2012). Cutaneous manifestations of dabrafenib (GSK2118436): a selective inhibitor of mutant BRAF in patients with metastatic melanoma. Br J Dermatol 167: 1153-1160.
3. Arnault JP, Mateus C, Escudier B, Tomasic G, Wechsler J, Hollville E, et al. (2012). Skin tumors induced by sorafenib; paradoxic RAS-RAF pathway activation and oncogenic mutations of HRAS, TP53, and TGFBR1. Clin Cancer Res 18: 263-272.
4. Arumugam T, Ramachandran V, Fournier KF, Wang H, Marquis L, Abbruzzese JL, et al. (2009). Epithelial to mesenchymal transition contributes to drug resistance in pancreatic cancer. Cancer Res 69: 5820-5828.
5. Balmanno K, Cook SJ, (2009). Tumour cell survival signalling by the ERK1/2 pathway. Cell Death Differ 16: 368-377.
6. Balmanno K, Chell SD, Gillings AS, Hayat S, Cook SJ, (2009). Intrinsic resistance to the MEK1/2 inhibitor AZD6244 (ARRY-142886) is associated with weak ERK1/2 signalling and/or strong PI3K signalling in colorectal cancer cell lines. Int J Cancer 125: 2332-2341.
7. Basile KJ, Aplin AE, (2012). Downregulation of Noxa by RAF/MEK inhibition counteracts cell death response in mutant B-RAF melanoma cells. Am J Cancer Res 2: 726-735.
8. Bennouna J, Lang I, Valladares-Ayerbes M, Boer K, Adenis A, Escudero P, et al. (2011). A Phase II, open-label, randomised study to assess the efficacy and safety of the MEK1/2 inhibitor AZD6244 (ARRY-142886) versus capecitabine monotherapy in patients with colorectal cancer who have failed one or two prior chemotherapeutic regimens. Invest New Drugs 29: 1021-1028.
9. Bock C, Lengauer T, (2012). Managing drug resistance in cancer: lessons from HIV therapy. Nat Rev Cancer 12: 494-501.
10. Bodoky G, Timcheva C, Spigel DR, La Stella PJ, Ciuleanu TE, Pover G, et al. (2012). A phase II open-label randomized study to assess the efficacy and safety of selumetinib (AZD6244 [ARRY-142886]) versus capecitabine in patients with advanced or metastatic pancreatic cancer who have failed first-line gemcitabine therapy. Invest New Drugs 30: 1216-1223.
11. Bollag G, Tsai J, Zhang J, Zhang C, Ibrahim P, Nolop K, et al. (2012). Vemurafenib: the first drug approved for BRAF-mutant cancer. Nat Rev Drug Discov 11: 873-886.
12. Bonni A, Brunet A, West AE, Datta SR, Takasu MA, Greenberg ME, (1999). Cell survival promoted by the Ras-MAPK signaling pathway by transcription- dependent and -independent mechanisms. Science 286: 1358-1362.
13. Booy EP, Henson ES, Gibson SB, (2011). Epidermal growth factor regulates Mcl-1 expression through the MAPK-Elk-1 signalling pathway contributing to cell survival in breast cancer. Oncogene 30: 2367-2378.
14. Bouchard C, Thieke K, Maier A, Saffrich R, Hanley-Hyde J, Ansorge W, et al. (1999). Direct induction of cyclin D2 by Myc contributes to cell cycle progression and sequestration of p27. EMBO J 18: 5321-5333.
15. Boucher MJ, Morisset J, Vachon PH, Reed JC, Lainé J, Rivard N, (2000). MEK/ERK signaling pathway regulates the expression of Bcl-2, Bcl-xL, and Mcl-1 and promotes survival of human pancreatic cancer cells. J Cell Biochem 79: 355-369.
16. Callahan MK, Rampal R, Harding JJ, Klimek VM, Chung YR, Merghoub T, et al. (2012). Progression of RAS-mutant leukemia during RAF inhibitor treatment. N Engl J Med 367: 2316-2321.
17. Capdeville R, Buchdunger E, Zimmermann J, Matter A, (2002). Glivec (STI571, imatinib), a rationally developed, targeted anticancer drug. Nat Rev Drug Discov 1: 493-502.
18. Chanan-Khan AA, Niesvizky R, Hohl RJ, Zimmerman TM, Christiansen NP, Schiller GJ, et al. (2009). Phase III randomised study of dexamethasone with or without oblimersen sodium for patients with advanced multiple myeloma. Leuk Lymphoma 50: 559-565.
19. Chapman P, Metz D, Sepulveda A, Uehara T, Rustgi A, Nathanson KL, et al. (2012). Development of colonic adenomas and gastric polyps in BRAF mutant melanoma patients treated with vemurafenib. Pigment Cell Melanoma Res 25: 847.
20. Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J, et al. (2011). Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 364: 2507-2516.
21. Chipuk JE, Moldoveanu T, Llambi F, Parsons MJ, Green DR, (2010). The BCL-2 family reunion. Mol Cell 37: 299-310.
22. Chonghaile TN, Letai A, (2008). Mimicking the BH3 domain to kill cancer cells. Oncogene 27: S149-S157.
23. Clavel F, Hance AJ, (2004). HIV drug resistance. N Engl J Med 350: 1023-1035.
24. Cobrinik D, (2005). Pocket proteins and cell cycle control. Oncogene 24: 2796-2809.
25. Corcoran RB, Dias-Santagata D, Bergethon K, Iafrate AJ, Settleman J, Engelman JA, (2010). BRAF gene amplification can promote acquired resistance to MEK inhibitors in cancer cells harboring the BRAF V600E mutation. Sci Signal 3: ra84.
26. Corcoran RB, Ebi H, Turke AB, Coffee EM, Nishino M, Cogdill AP, et al. (2012). EGFR-mediated re-activation of MAPK signaling contributes to insensitivity of BRAF mutant colorectal cancers to RAF inhibition with vemurafenib. Cancer Discov 2: 227-235.
27. Corcoran RB, Cheng KA, Hata AN, Faber AC, Ebi H, Coffee EM, et al. (2013). Synthetic lethal interaction of combined BCL-XL and MEK inhibition promotes tumor regressions in KRAS mutant cancer models. Cancer Cell 23: 121-128.
28. Cragg MS, Kuroda J, Puthalakath H, Huang DC, Strasser A, (2007). Gefitinib-induced killing of NSCLC cell lines expressing mutant EGFR requires BIM and can be enhanced by BH3 mimetics. Plos Med 4: 1681-1689.
29. Cragg MS, Jansen ES, Cook M, Harris C, Strasser A, Scott CL, (2008). Treatment of B-RAF mutant human tumor cells with a MEK inhibitor requires Bim and is enhanced by a BH3 mimetic. J Clin Invest 118: 3651-3659.
30. Das Thakur M, Salangsang F, Landman AS, Sellers WR, Pryer NK, Levesque MP, et al. (2013). Modelling vemurafenib resistance in melanoma reveals a strategy to forestall drug resistance. Nature 494: 251-255.
31. Datta SR, Dudek H, Tao X, Masters S, Fu H, Gotoh Y, et al. (1997). Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell 91: 231-241.
32. Davies BR, Logie A, McKay JS, Martin P, Steele S, Jenkins R, et al. (2007). AZD6244 (ARRY-142886), a potent inhibitor of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 1/2 kinases: mechanism of action in vivo, pharmacokinetic/ pharmacodynamic relationship, and potential for combination in preclinical models. Mol Cancer Ther 6: 2209-2219.
33. Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, et al. (2002). Mutations of the BRAF gene in human cancer. Nature 417: 949-954.
34. van Delft MF, Wei AH, Mason KD, Vandenberg CJ, Chen L, Czabotar PE, et al. (2006). The BH3 mimetic ABT-737 targets selective Bcl-2 proteins and efficiently induces apoptosis via Bak/Bax if Mcl-1 is neutralized. Cancer Cell 10: 389-399.
35. Delmas C, Manenti S, Boudjelal A, Peyssonnaux C, Eychene A, Darbon JM, (2001). The p42/p44 mitogen-activated protein kinase activation triggers p27Kip1 degradation independently of CDK2/cyclin E in NIH 3T3 cells. J Biol Chem 276: 34958-34965.
36. Dijkers PF, Medema RH, Lammers JW, Koenderman L, Coffer PJ, (2000). Expression of the proapoptotic Bcl-2 family member Bim is regulated by the forkhead transcription factor FKHR-L1. Curr Biol 10: 1201-1204.
37. Domina AM, Vrana JA, Gregory MA, Hann SR, Craig RW, (2004). MCL1 is phosphorylated in the PEST region and stabilized upon ERK activation in viable cells, and at additional sites with cytotoxic okadaic acid or taxol. Oncogene 23: 5301-5315.
38. Downward J, (2003). Targeting RAS signalling pathways in cancer therapy. Nat Rev Cancer 3: 11-22.
39. Elgendy M, Sheridan C, Brumatti G, Martin SJ, (2011). Oncogenic Ras-induced expression of Noxa and Beclin-1 promotes autophagic cell death and limits clonogenic survival. Mol Cell 42: 23-35.
40. Emery CM, Vijayendran KG, Zipser MC, Sawyer AM, Niu L, Kim JJ, et al. (2009). MEK1 mutations confer resistance to MEK and B-RAF inhibition. Proc Natl Acad Sci U S A 106: 20411-20416.
41. Escrivà M, Peiró S, Herranz N, Villagrasa P, Dave N, Montserrat-Sentís B, et al. (2008). Repression of PTEN phosphatase by Snail1 transcriptional factor during gamma radiation-induced apoptosis. Mol Cell Biol 28: 1528-1540.
42. Ewings KE, Hadfield-Moorhouse K, Wiggins CM, Wickenden JA, Balmanno K, Gilley R, et al. (2007). ERK1/2-dependent phosphorylation of BimEL promotes its rapid dissociation from Mcl-1 and Bcl-xL. EMBO J 26: 2856-2867.
43. Faber AC, Corcoran RB, Ebi H, Sequist LV, Waltman BA, Chung E, et al. (2011). BIM expression in treatment-naive cancers predicts responsiveness to kinase inhibitors. Cancer Discov 1: 352-365.
44. Fang X, Yu S, Eder A, Mao M, Bast JRC, Boyd D, et al. (1999). Regulation of BAD phosphorylation at serine 112 by the Ras-mitogen-activated protein kinase pathway. Oncogene 18: 6635-6640.
45. Fariña-Sarasqueta A, van Lijnschoten G, Moerland E, Creemers GJ, Lemmens VE, Rutten HJ, et al. (2010). The BRAF V600E mutation is an independent prognostic factor for survival in stage II and stage III colon cancer patients. Ann Oncol 21: 2396-2402.
46. Fox W, Ellard GA, Mitchison DA, (1999). Studies on the treatment of tuberculosis undertaken by the British Medical Research Council tuberculosis units, 1946-1986, with relevant subsequent publications. Int J Tuberc Lung Dis 3: S231-S279.
47. Fujita N, Sato S, Tsuruo T, (2003). Phosphorylation of p27Kip1 at threonine 198 by p90 ribosomal protein S6 kinases promotes its binding to 14-3-3 and cytoplasmic localization. J Biol Chem 278: 49254-49260.
48. Del Gaizo Moore V, Brown JR, Certo M, Love TM, Novina CD, Letai A, (2007). Chronic lymphocytic leukemia requires BCL2 to sequester prodeath BIM, explaining sensitivity to BCL2 antagonist ABT-737. J Clin Invest 117: 112-121.
49. Galaktionov K, Chen XC, Beach D, (1996). Cdc25 cell-cycle phosphatase as a target of c-myc. Nature 382: 511-517.
50. Gartel AL, Ye X, Goufman E, Shianov P, Hay N, Najmabadi F, et al. (2001). Myc represses the p21(WAF1/CIP1) promoter and interacts with Sp1/Sp3. Proc Natl Acad Sci U S A 98: 4510-4515.
51. Girotti MR, Pedersen M, Sanchez-Laorden B, Viros A, Turajlic S, Niculescu-Duvaz D, et al. (2013). Inhibiting EGF receptor or SRC family kinase signaling overcomes BRAF inhibitor resistance in melanoma. Cancer Discov 3: 158-167.
52. Glickman MS, Sawyers CL, (2012). Converting cancer therapies into cures: lessons from infectious diseases. Cell 148: 1089-1098.
53. Greger JG, Eastman SD, Zhang V, Bleam MR, Hughes AM, Smitheman KN, et al. (2012). Combinations of BRAF, MEK, and PI3K/mTOR inhibitors overcome acquired resistance to the BRAF inhibitor GSK2118436 dabrafenib, mediated by NRAS or MEK mutations. Mol Cancer Ther 11: 909-920.
54. Hainsworth JD, Cebotaru CL, Kanarev V, Ciuleanu TE, Damyanov D, Stella P, et al. (2010). A phase II, open-label, randomized study to assess the efficacy and safety of AZD6244 (ARRY-142886) versus pemetrexed in patients with non-small cell lung cancer who have failed one or two prior chemotherapeutic regimens. J Thorac Oncol 5: 1630-1636.
55. Hatzivassiliou G, Song K, Yen I, Brandhuber BJ, Anderson DJ, Alvarado R, et al. (2010). RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth. Nature 464: 431-435.
56. Hatzivassiliou G, Liu B, O'Brien C, Spoerke JM, Hoeflich KP, Haverty PM, et al. (2012). ERK inhibition overcomes acquired resistance to MEK inhibitors. Mol Cancer Ther 11: 1143-1154.
57. Hayes DN, Lucas AS, Tanvetyanon T, Krzyzanowska MK, Chung CH, Murphy BA, et al. (2012). Phase II efficacy and pharmacogenomic study of Selumetinib (AZD6244; ARRY-142886) in iodine-131 refractory papillary thyroid carcinoma with or without follicular elements. Clin Cancer Res 18: 2056-2065.
58. Heidorn SJ, Milagre C, Whittaker S, Nourry A, Niculescu-Duvas I, Dhomen N, et al. (2010). Kinase-dead BRAF and oncogenic RAS cooperate to drive tumor progression through CRAF. Cell 140: 209-221.
59. Hermeking H, Rago C, Schuhmacher M, Li Q, Barrett JF, Obaya AJ, et al. (2000). Identification of CDK4 as a target of c-MYC. Proc Natl Acad Sci U S A 97: 2229-2234.
60. Jänne PA, Shaw AT, Pereira JR, Jeannin G, Vansteenkiste J, Barrios C, et al. (2012). Selumetinib plus docetaxel for KRAS-mutant advanced non-small-cell lung cancer: a randomised, multicentre, placebo-controlled, phase 2 study. Lancet Oncol 14: 38-47.
61. Johannessen CM, Boehm JS, Kim SY, Thomas SR, Wardwell L, Johnson LA, et al. (2010). COT drives resistance to RAF inhibition through MAP kinase pathway reactivation. Nature 468: 968-972.
62. Joseph EW, Pratilas CA, Poulikakos PI, Tadi M, Wang W, Taylor BS, et al. (2010). The RAF inhibitor PLX4032 inhibits ERK signaling and tumor cell proliferation in a V600E BRAF-selective manner. Proc Natl Acad Sci U S A 107: 14903-14908.
63. Kirkin V, Joos S, Zörnig M, (2004). The role of Bcl-2 family members in tumorigenesis. Biochim Biophys Acta 1644: 229-249.
64. Kirkwood JM, Bastholt L, Robert C, Sosman J, Larkin J, Hersey P, et al. (2012). Phase II, open-label, randomized trial of the MEK1/2 inhibitor selumetinib as monotherapy versus temozolomide in patients with advanced melanoma. Clin Cancer Res 18: 555-567.
65. Klasa RJ, Gillum AM, Klem RE, Frankel SR, (2002). Oblimersen Bcl-2 antisense: facilitating apoptosis in anticancer treatment. Antisense Nucleic Acid Drug Dev 12: 193-213.
66. Konopleva M, Contractor R, Tsao T, Samudio I, Ruvolo PP, Kitada S, et al. (2006). Mechanisms of apoptosis sensitivity and resistance to the BH3 mimetic ABT-737 in acute myeloid leukemia. Cancer Cell 10: 193-213.
67. Konopleva M, Watt J, Contractor R, Tsao T, Harris D, Estrov Z, et al. (2008). Mechanisms of antileukemic activity of the novel Bcl-2 homology domain-3 mimetic GX15-070 (obatoclax). Cancer Res 68: 3413-3420.
68. Konopleva M, Milella M, Ruvolo P, Watts JC, Ricciardi MR, Korchin B, et al. (2012). MEK inhibition enhances ABT-737-induced leukemia cell apoptosis via prevention of ERK-activated MCL-1 induction and modulation of MCL-1/BIM complex. Leukemia 26: 778-787.
69. Kopetz S, Desai J, Chan E, Hecht JR, O'Dwyer PJ, Lee RJ, et al. (2010). PLX4032 in metastatic colorectal cancer patients with mutant BRAF tumors. J Clin Oncol 28: Abstract 3534.
70. Kuroda J, Puthalakath H, Cragg MS, Kelly PN, Bouillet P, Huang DC, et al. (2006). Bim and Bad mediate imatinib-induced killing of Bcr/Abl+ leukemic cells, and resistance due to their loss is overcome by a BH3 mimetic. Proc Natl Acad Sci U S A 103: 14907-14912.
71. Kuwana T, Bouchier-Hayes L, Chipuk JE, Bonzon C, Sullivan BA, Green DR, et al. (2005). BH3 domains of BH3-only proteins differentially regulate Bax-mediated mitochondrial membrane permeabilization both directly and indirectly. Mol Cell 17: 525-535.
72. Le K, Blomain E, Rodeck U, Aplin AE, (2013). Selective RAF inhibitor impairs ERK1/2 phosphorylation and growth in mutant NRAS, vemurafenib-resistant melanoma cells. Pigment Cell Melanoma Res doi: 10.1111/pcmr.12092
73. Ley R, Balmanno K, Hadfield K, Weston C, Cook SJ, (2003). Activation of the ERK1/2 signaling pathway promotes phosphorylation and proteasome-dependent degradation of the BH3-only protein, Bim. J Biol Chem 278: 18811-18816.
74. Lito P, Pratilas CA, Joseph EW, Tadi M, Halilovic E, Zubrowski M, et al. (2012). Relief of profound feedback inhibition of mitogenic signaling by RAF inhibitors attenuates their activity in BRAFV600E melanomas. Cancer Cell 22: 668-682.
75. Little AS, Balmanno K, Sale MJ, Newman S, Dry JR, Hampson M, et al. (2011). Amplification of the driving oncogene, KRAS or BRAF, underpins acquired resistance to MEK1/2 inhibitors in colorectal cancer cells. Sci Signal 4: ra17.
76. Little AS, Smith PD, Cook SJ, (2013). Mechanisms of acquired resistance to ERK1/2 pathway inhibitors. Oncogene 32: 1207-1215.
77. Lopez J, Hesling C, Prudent J, Popgeorgiev N, Gadet R, Mikaelian I, et al. (2012). Src tyrosine kinase inhibits apoptosis through the Erk1/2-dependent degradation of the death accelerator Bik. Cell Death Differ 19: 1459-1469.
78. Ma Y, Zhang C, Habets G, Burton EA, Wong B, Nguyen H, et al. (2011). BRAF inhibitors upregulate EGFR ligands: a molecular link to RAF inhibitor-induced cutaneous squamous cell carcinomas. Mol Cancer Ther 10: Abstract A229.
79. Maurer U, Charvet C, Wagman AS, Dejardin E, Green DR, (2006). Glycogen synthase kinase-3 regulates mitochondrial outer membrane permeabilization and apoptosis by destabilization of MCL-1. Mol Cell 21: 749-760.
80. Meloche S, Pouysségur J, (2007). The ERK1/2 mitogen-activated protein kinase pathway as a master regulator of the G1- to S-phase transition. Oncogene 26: 3227-3239.
81. Montagut C, Sharma SV, Shioda T, McDermott U, Ulman M, Ulkus LE, et al. (2008). Elevated CRAF as a potential mechanism of acquired resistance to BRAF inhibition in melanoma. Cancer Res 68: 4853-4861.
82. Nazarian R, Shi H, Wang Q, Kong X, Koya RC, Lee H, et al. (2010). Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation. Nature 468: 973-977.
83. O'Brien SM, Claxton DF, Crump M, Faderl S, Kipps T, Keating MJ, et al. (2009a). Phase I study of obatoclax mesylate (GX15-070), a small molecule pan-Bcl-2 family antagonist, in patients with advanced chronic lymphocytic leukemia. Blood 113: 299-305.
84. O'Brien S, Moore JO, Boyd TE, Larratt LM, Skotnicki AB, Koziner B, et al. (2009b). 5-year survival in patients with relapsed or refractory chronic lymphocytic leukemia in a randomized, phase III trial of fludarabine plus cyclophosphamide with or without Oblimersen. J Clin Oncol 27: 5208-5212.
85. Oltersdorf T, Elmore SW, Shoemaker AR, Armstrong RC, Augeri DJ, Belli BA, et al. (2005). An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature 435: 677-681.
86. Paik PK, Rudin CM, Brown A, Rizvi NA, Takebe N, Travis W, et al. (2010). A phase I study of obatoclax mesylate, a Bcl-2 antagonist, plus topotecan in solid tumor malignancies. Cancer Chemother Pharmacol 66: 1079-1085.
87. Paik PK, Rudin CM, Pietanza MC, Brown A, Rizvi NA, Takebe N, et al. (2011). A phase II study of obatoclax mesylate, a Bcl-2 antagonist, plus topotecan in relapsed small cell lung cancer. Lung Cancer 74: 481-485.
88. Patel SP, Lazar AJ, Papadopoulos NE, Liu P, Infante JR, Glass MR, et al. (2013). Clinical responses to selumetinib (AZD6244; ARRY-142886)-based combination therapy stratified by gene mutations in patients with metastatic melanoma. Cancer 119: 799-805.
89. del Peso L, González-García M, Page C, Herrera R, Nuñez G, (1997). Interleukin-3-induced phosphorylation of BAD through the protein kinase Akt. Science 278: 687-689.
90. Poulikakos PI, Zhang C, Bollag G, Shokat KM, Rosen N, (2010). RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF. Nature 464: 427-430.
91. Poulikakos PI, Persaud Y, Janakiraman M, Kong X, Ng C, Moriceau G, et al. (2011). RAF inhibitor resistance is mediated by dimerization of aberrantly spliced BRAF(V600E). Nature 480: 387-390.
92. Prahallad A, Sun C, Huang S, Di Nicolantonio F, Salazar R, Zecchin D, et al. (2012). Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR. Nature 483: 100-103.
93. Qian J, Zou Y, Rahman JS, Lu B, Massion PP, (2009). Synergy between phosphatidylinositol 3-kinase/Akt pathway and Bcl-xL in the control of apoptosis in adenocarcinoma cells of the lung. Mol Cancer Ther 8: 101-109.
94. Rahmani M, Aust MM, Attkisson E, Williams DC Jr, Ferreira-Gonzalez A, Grant S, (2013). Dual inhibition of Bcl-2 and Bcl-xL strikingly enhances PI3K inhibition-induced apoptosis in human myeloid leukemia cells through a GSK3- and Bim-dependent mechanism. Cancer Res 73: 1340-1351.
95. Richman SD, Seymour MT, Chambers P, Elliott F, Daly CL, Meade AM, et al. (2009). KRAS and BRAF mutations in advanced colorectal cancer are associated with poor prognosis but do not preclude benefit from oxaliplatin or irinotecan: results from the MRC FOCUS trial. J Clin Oncol 27: 5931-5937.
96. Rivard N, Boucher MJ, Asselin C, L'Allemain G, (1999). MAP kinase cascade is required for p27 downregulation and S phase entry in fibroblasts and epithelial cells. Am J Physiol 277: C652-C664.
97. Roberts AW, Seymour JF, Brown JR, Wierda WG, Kipps TJ, Khaw SL, et al. (2012). Substantial susceptibility of chronic lymphocytic leukemia to BCL2 inhibition: results of a phase I study of navitoclax in patients with relapsed or refractory disease. J Clin Oncol 30: 488-496.
98. Robson EJ, Khaled WT, Abell K, Watson CJ, (2006). Epithelial-to- mesenchymal transition confers resistance to apoptosis in three murine mammary epithelial cell lines. Differentiation 74: 254-264.
99. Rudin CM, Hann CL, Garon EB, Ribeiro de Oliveira M, Bonomi PD, Camidge DR, et al. (2012). Phase II study of single-agent navitoclax (ABT-263) and biomarker correlates in patients with relapsed small cell lung cancer. Clin Cancer Res 18: 3163-3169.
100. Sale MJ, Cook SJ, (2013). The BH3-mimetic ABT-263 synergises with the MEK1/2 inhibitor selumetinib/AZD6244 to promote BIM-dependent tumour cell death and inhibit acquired resistance. Biochem J 450: 285-294.
101. Scheid MP, Schubert KM, Duronio V, (1999). Regulation of bad phosphorylation and association with Bcl-x(L) by the MAPK/Erk kinase. J Biol Chem 274: 31108-31113.
102. Sears R, Nuckolls F, Haura E, Taya Y, Tamai K, Nevins JR, (2000). Multiple Ras-dependent phosphorylation pathways regulate Myc protein stability. Genes Dev 14: 2501-2514.
103. Sequist LV, Lynch TJ, (2008). EGFR tyrosine kinase inhibitors in lung cancer: an evolving story. Annu Rev Med 59: 429-442.
104. Shao Y, Aplin AE, (2010). Akt3-mediated resistance to apoptosis in B-RAF-targeted melanoma cells. Cancer Res 70: 6670-6681.
105. Shao Y, Aplin AE, (2012). ERK2 phosphorylation of serine 77 regulates Bmf pro-apoptotic activity. Cell Death Dis 3: e253.
106. She QB, Ma WY, Zhong S, Dong Z, (2002). Activation of JNK1, RSK2, and MSK1 is involved in serine 112 phosphorylation of Bad by ultraviolet B radiation. J Biol Chem 277: 24039-24048.
107. Sheridan C, Brumatti G, Martin SJ, (2008). Oncogenic B-RafV600E inhibits apoptosis and promotes ERK-dependent inactivation of Bad and Bim. J Biol Chem 283: 22128-22135.
108. Sheridan C, Brumatti G, Elgendy M, Brunet M, Martin SJ, (2010). An ERK-dependent pathway to Noxa expression regulates apoptosis by platinum-based chemotherapeutic drugs. Oncogene 29: 6428-6441.
109. Shi H, Moriceau G, Kong X, Lee MK, Lee H, Koya RC, et al. (2012). Melanoma whole-exome sequencing identifies (V600E) B-RAF amplification-mediated acquired B-RAF inhibitor resistance. Nat Commun 3: 724.
110. Shimamura A, Ballif BA, Richards SA, Blenis J, (2000). Rsk1 mediates a MEK-MAP kinase cell survival signal. Curr Biol 10: 127-135.
111. Smalley KS, Lioni M, Dalla Palma M, Xiao M, Desai B, Egyhazi S, et al. (2008). Increased cyclin D1 expression can mediate BRAF inhibitor resistance in BRAF V600E-mutated melanomas. Mol Cancer Ther 7: 2876-2883.
112. Solit DB, Garraway LA, Pratilas CA, Sawai A, Getz G, Basso A, et al. (2006). BRAF mutation predicts sensitivity to MEK inhibition. Nature 439: 358-362.
113. Sosman JA, Kim KB, Schuchter L, Gonzalez R, Pavlick AC, Weber JS, et al. (2012). Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. N Engl J Med 366: 707-714.
114. Spender LC, Inman GJ, (2012). Phosphoinositide 3-kinase/AKT/mTORC1/2 signaling determines sensitivity of Burkitt's lymphoma cells to BH3 mimetics. Mol Cancer Res 10: 347-359.
115. Su F, Viros A, Milagre C, Trunzer K, Bollag G, Spleiss O, et al. (2012a). RAS mutations in cutaneous squamous-cell carcinomas in patients treated with BRAF inhibitors. N Engl J Med 366: 207-215.
116. Su F, Bradley WD, Wang Q, Yang H, Xu L, Higgins B, et al. (2012b). Resistance to selective BRAF inhibition can be mediated by modest upstream pathway activation. Cancer Res 72: 969-978.
117. Tait SW, Green DR, (2010). Mitochondria and cell death: outer membrane permeabilization and beyond. Nat Rev Mol Cell Biol 11: 621-632.
118. Tan N, Wong M, Nannini MA, Hong R, Lee LB, Price S, et al. (2013). Bcl-2/Bcl-xL inhibition increases the efficacy of Mek inhibition alone and in combination with PI3 Kinase inhibition in lung and pancreatic tumor models. Mol Cancer Ther doi: 10.1158/1535-7163.MCT-12-0949
119. Tan Y, Ruan H, Demeter MR, Comb MJ, (1999). p90(RSK) blocks bad-mediated cell death via a protein kinase C-dependent pathway. J Biol Chem 274: 34859-34867.
120. Tiacci E, Trifonov V, Schiavoni G, Holmes A, Kern W, Martelli MP, et al. (2011). BRAF mutations in hairy-cell leukemia. N Engl J Med 364: 2305-2315.
121. Tiwari N, Gheldof A, Tatari M, Christofori G, (2012). EMT as the ultimate survival mechanism of cancer cells. Semin Cancer Biol 22: 194-207.
122. Tol J, Nagtegaal ID, Punt CJ, (2009). BRAF mutation in metastatic colorectal cancer. N Engl J Med 361: 98-99.
123. Townsend KJ, Zhou P, Qian L, Bieszczad CK, Lowrey CH, Yen A, et al. (1999). Regulation of MCL1 through a serum response factor/Elk-1-mediated mechanism links expression of a viability-promoting member of the BCL2 family to the induction of hematopoietic cell differentiation. J Biol Chem 274: 1801-1813.
124. Tse C, Shoemaker AR, Adickes J, Anderson MG, Chen J, Jin S, et al. (2008). ABT-263: a potent and orally bioavailable Bcl-2 family inhibitor. Cancer Res 68: 3421-3428.
125. VanBrocklin MW, Verhaegen M, Soengas MS, Holmen SL, (2009). Mitogen-activated protein kinase inhibition induces translocation of Bmf to promote apoptosis in melanoma. Cancer Res 69: 1985-1994.
126. Vega S, Morales AV, Ocaña OH, Valdés F, Fabregat I, Nieto MA, (2004). Snail blocks the cell cycle and confers resistance to cell death. Genes Dev 18: 1131-1143.
127. Vickers ER, Kasza A, Kurnaz IA, Seifert A, Zeef LA, O'donnell A, et al. (2004). Ternary complex factor-serum response factor complex-regulated gene activity is required for cellular proliferation and inhibition of apoptotic cell death. Mol Cell Biol 24: 10340-103451.
128. Villanueva J, Vultur A, Lee JT, Somasundaram R, Fukunaga-Kalabis M, Cipolla AK, et al. (2010). 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.
129. Wagle N, Emery C, Berger MF, Davis MJ, Sawyer A, Pochanard P, et al. (2011). Dissecting therapeutic resistance to RAF inhibition in melanoma by tumor genomic profiling. J Clin Oncol 29: 3085-3096.
130. Wang C, Youle RJ, (2012). Predominant requirement of Bax for apoptosis in HCT116 cells is determined by Mcl-1's inhibitory effect on Bak. Oncogene 31: 3177-3189.
131. Wang H, Daouti S, Li WH, Wen Y, Rizzo C, Higgins B, et al. (2011). Identification of the MEK1(F129L) activating mutation as a potential mechanism of acquired resistance to MEK inhibition in human cancers carrying the B-RafV600E mutation. Cancer Res 71: 5535-5545.
132. Wang JM, Chao JR, Chen W, Kuo ML, Yen JJ, Yang-Yen HF, (1999). The antiapoptotic gene mcl-1 is up-regulated by the phosphatidylinositol 3-kinase/Akt signaling pathway through a transcription factor complex containing CREB. Mol Cell Biol 19: 6195-6206.
133. Wang YF, Jiang CC, Kiejda KA, Gillespie S, Zhang XD, Hersey P, (2007). Apoptosis induction in human melanoma cells by inhibition of MEK is caspase-independent and mediated by the Bcl-2 family members PUMA, Bim, and Mcl-1. Clin Cancer Res 13: 4934-4942.
134. Whittaker S, Kirk R, Hayward R, Zambon A, Viros A, Cantarino N, et al. (2010). Gatekeeper mutations mediate resistance to BRAF-targeted therapies. Sci Transl Med 2: 35ra41.
135. Wickenden JA, Jin H, Johnson M, Gillings AS, Newson C, Austin M, et al. (2008). Colorectal cancer cells with the BRAF(V600E) mutation are addicted to the ERK1/2 pathway for growth factor-independent survival and repression of BIM. Oncogene 27: 7150-7161.
136. Wilson B, Mochon E, Boxer L, (1996). Induction of bcl-2 expression by phosphorylated CREB proteins during B- cell activation and rescue from apoptosis. Mol Cell Biol 16: 5546-5556.
137. Wilson WH, O'Connor OA, Czuczman MS, LaCasce AS, Gerecitano JF, Leonard JP, et al. (2010). Navitoclax, a targeted high-affinity inhibitor of BCL-2, in lymphoid malignancies: a phase 1 dose-escalation study of safety, pharmacokinetics, pharmacodynamics, and antitumour activity. Lancet Oncol 11: 1149-1159.
138. Wroblewski D, Mijatov B, Mohana-Kumaran N, Lai F, Gallagher SJ, Haass NK, et al. (2013). The BH3-mimetic ABT-737 sensitizes human melanoma cells to apoptosis induced by selective BRAF inhibitors but does not reverse acquired resistance. Carcinogenesis 34: 237-247.
139. Xing M, (2005). BRAF mutation in thyroid cancer. Endocr Relat Cancer 12: 245-262.
140. Yadav V, Zhang X, Liu J, Estrem S, Li S, Gong XQ, et al. (2012). Reactivation of mitogen-activated protein kinase (MAPK) pathway by FGF receptor 3 (FGFR3)/Ras mediates resistance to vemurafenib in human B-RAF V600E mutant melanoma. J Biol Chem 287: 28087-28098.
141. Yang JY, Zong CS, Xia WY, Yamaguchi H, Ding QQ, Xie XM, et al. (2008). ERK promotes tumorigenesis by inhibiting FOXO3a via MDM2-mediated degradation. Nat Cell Biol 10: 138-148.
142. Yecies D, Carlson NE, Deng J, Letai A, (2010). Acquired resistance to ABT-737 in lymphoma cells that up-regulate MCL-1 and BFL-1. Blood 115: 3304-3313.
143. Yeh TC, Marsh V, Bernat BA, Ballard J, Colwell H, Evans RJ, et al. (2007). Biological Characterization of ARRY-142886 (AZD6244), a potent, highly selective mitogen-activated protein kinase kinase 1/2 Inhibitor. Clin Cancer Res 13: 1576-1583.
144. You H, Pellegrini M, Tsuchihara K, Yamamoto K, Hacker G, Erlacher M, et al. (2006). FOXO3a-dependent regulation of Puma in response to cytokine/growth factor withdrawal. J Exp Med 203: 1657-1663.
145. Zha J, Harada H, Yang E, Jockel J, Korsmeyer SJ, (1996). Serine phosphorylation of death agonist BAD in response to survival factor results in binding to 14-3-3 not BCL-X(L). Cell 87: 619-628.
146. Zhai D, Jin C, Satterthwait AC, Reed JC, (2006). Comparison of chemical inhibitors of antiapoptotic Bcl-2-family proteins. Cell Death Differ 13: 1419-1421.
147. Zhang W, Konopleva M, Ruvolo VR, McQueen T, Evans RL, Bornmann WG, et al. (2008). Sorafenib induces apoptosis of AML cells via Bim-mediated activation of the intrinsic apoptotic pathway. Leukemia 22: 808-818.