Rational combination of a MEK inhibitor, selumetinib, and the wnt/calcium pathway modulator, cyclosporin a, in preclinical models of colorectal cancer

Clinical Cancer Research

Volumn 19, Issue 15, 2013, Pages 4149-4162

  Spreafico, Anna ^a   Tentler, John J ^a   Pitts, Todd M ^a   Tan, Aik Choon ^a   Gregory, Mark A ^b   Arcaroli, John J ^a   Klauck, Peter J ^a   McManus, Martine C ^b   Hansen, Ryan J ^e   Kim, Jihye ^a   Micel, Lindsey N ^a,d   Selby, Heather M ^a   Newton, Timothy P ^a   McPhillips, Kelly L ^a   Gustafson, Daniel L ^e   DeGregori, James V ^b   Messersmith, Wells A ^a   Winn, Robert A ^c   Eckhardt, S Gail ^a  

^a UNIVERSITY OF COLORADO SCHOOL OF MEDICINE   (United States)

^b Department of Molecular Biology ^*  (United States)

^c UNIVERSITY OF COLORADO   (United States)

^d UNIVERSITY OF COLORADO   (United States)

^e Department of Environmental and Radiological Health Sciences   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CALCIUM ION; CASPASE 3; CASPASE 7; CYCLOSPORIN A; FRIZZLED PROTEIN; FUMAGILLOL CHLOROACETYLCARBAMATE; LIGAND; LUCIFERASE; MULTIDRUG RESISTANCE PROTEIN; SELUMETINIB; SHORT HAIRPIN RNA; TRANSCRIPTION FACTOR NFAT; WNT PROTEIN; BENZIMIDAZOLE DERIVATIVE; CALCIUM; CYCLOSPORIN; KRAS PROTEIN, HUMAN; MITOGEN ACTIVATED PROTEIN KINASE KINASE KINASE; ONCOPROTEIN; PROTEIN KINASE INHIBITOR; RAS PROTEIN;

ANIMAL CELL; ANTIPROLIFERATIVE ACTIVITY; APOPTOSIS; ARTICLE; CALCIUM SIGNALING; CANCER CELL CULTURE; CANCER COMBINATION CHEMOTHERAPY; CANCER INHIBITION; CANCER PATIENT; CLINICAL ARTICLE; COLORECTAL CANCER; CONTROLLED STUDY; DRUG POTENTIATION; ENZYME ACTIVITY; FZD2 GENE; FZD3 GENE; GENE; GENE CONSTRUCT; GENE SET ENRICHMENT ANALYSIS; GENETIC ANALYSIS; HUMAN; HUMAN CELL; IC 50; IN VITRO STUDY; IN VIVO STUDY; MONOTHERAPY; NONHUMAN; PATIENT DERIVED TUMOR EXPLANT; PRIORITY JOURNAL; PROMOTER REGION; SIGNAL TRANSDUCTION; SYNTHETIC LETHALITY SCREEN ANALYSIS; TREATMENT DURATION; TREATMENT RESPONSE; TUMOR REGRESSION; WTN2B GENE; WTN5B GENE; ANTAGONISTS AND INHIBITORS; CELL PROLIFERATION; COLORECTAL NEOPLASMS; DRUG EFFECTS; DRUG SCREENING; GENETICS; METABOLISM; PATHOLOGY; TUMOR CELL LINE; WNT SIGNALING PATHWAY;

APOPTOSIS; BENZIMIDAZOLES; CALCIUM; CALCIUM SIGNALING; CELL LINE, TUMOR; CELL PROLIFERATION; COLORECTAL NEOPLASMS; CYCLOSPORINE; HUMANS; MAP KINASE KINASE KINASES; PROTEIN KINASE INHIBITORS; PROTO-ONCOGENE PROTEINS; RAS PROTEINS; SIGNAL TRANSDUCTION; WNT SIGNALING PATHWAY; XENOGRAFT MODEL ANTITUMOR ASSAYS;

EID: 84881223991     PISSN: 10780432     EISSN: 15573265     Source Type: Journal    
DOI: 10.1158/1078-0432.CCR-12-3140     Document Type: Article

References (59)

1. Chresta CM, Davies BR, Hickson I, Harding T, Cosulich S, Critchlow SE, et al. AZD8055 is a potent, selective, and orally bioavailable ATP-competitive mammalian target of rapamycin kinase inhibitor with in vitro and in vivo antitumor activity. Cancer Res 2010;70: 288-98.
2. Fransen K, Klintenas M, Osterstrom A, Dimberg J, Monstein HJ, Soderkvist P. Mutation analysis of the BRAF, ARAF and RAF-1 genes in human colorectal adenocarcinomas. Carcinogenesis 2004;25: 527-33.
3. Vaughn CP, Zobell SD, Furtado LV, Baker CL, Samowitz WS. Frequency of KRAS, BRAF, and NRAS mutations in colorectal cancer. Genes Chromosomes Cancer 2011;50:307-12.
4. Amado RG, Wolf M, Peeters M, Van Cutsem E, Siena S, Freeman DJ, et al. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol 2008;26:1626-34.
5. Bokemeyer C, Van Cutsem E, Rougier P, Ciardiello F, Heeger S, Schlichting M, et al. Addition of cetuximab to chemotherapy as first-line treatment for KRAS wild-type metastatic colorectal cancer: pooled analysis of the CRYSTAL and OPUS randomised clinical trials. Eur J Cancer 2012;48:1466-75.
6. Karapetis CS, Khambata-Ford S, Jonker DJ, O'Callaghan CJ, Tu D, Tebbutt NC, et al. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med 2008;359:1757-65.
7. Lievre A, Bachet JB, Le Corre D, Boige V, Landi B, Emile JF, et al. KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res 2006;66:3992-5.
8. Loupakis F, Ruzzo A, Cremolini C, Vincenzi B, Salvatore L, Santini D, et al. KRAS codon 61, 146 and BRAF mutations predict resistance to cetuximab plus irinotecan in KRAS codon 12 and 13 wild-type metastatic colorectal cancer. Br J Cancer 2009;101:715-21.
9. Bertrand FE, Steelman LS, Chappell WH, Abrams SL, Shelton JG, White ER, et al. Synergy between an IGF-1R antibody and Raf/MEK/ ERK and PI3K/Akt/mTOR pathway inhibitors in suppressing IGF-1R-mediated growth in hematopoietic cells. Leukemia 2006;20: 1254-60.
10. Corcoran R, Settleman J, Engelman J. Potential therapeutic strategies to overcome acquired resistance to BRAF or MEK inhibitors in BRAF mutant cancers. Oncotarget 2011;2:336-46.
11. Turke AB, Song Y, Costa C, Cook R, Arteaga CL, Asara JM, et al. MEK inhibition leads to PI3K/AKT activation by relieving a negative feedback on ERBB receptors. Cancer Res 2012;72:3228-37.
12. Adjei AA, Cohen RB, Franklin W, Morris C, Wilson D, Molina JR, et al. Phase I pharmacokinetic and pharmacodynamic study of the oral, small-molecule mitogen-Activated protein kinase kinase 1/2 inhibitor AZD6244 (ARRY-142886) in patients with advanced cancers. J Clin Oncol 2008;26:2139-46.
13. Balmanno K, Chell SD, Gillings AS, Hayat S, Cook SJ. 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 2009;125: 2332-41.
14. Bennouna J, Lang I, Valladares-Ayerbes M, Boer K, Adenis A, Escudero P, et al. 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 2011;29:1021-8.
15. Corcoran RB, Dias-Santagata D, Bergethon K, Iafrate AJ, Settleman J, Engelman JA. BRAF gene amplification can promote acquired resistance to MEK inhibitors in cancer cells harboring the BRAF V600E mutation. Sci Signal 2010;3:ra84.
16. Tentler JJ, Nallapareddy S, Tan AC, Spreafico A, Pitts TM, Morelli MP, et al. Identification of predictive markers of response to the MEK1/2 inhibitor selumetinib (AZD6244) in K-ras-mutated colorectal cancer. Mol Cancer Ther 2010;9:3351-62.
17. Bekaii-Saab T, Phelps MA, Li X, Saji M, Goff L, Kauh JS, et al. Multiinstitutional phase II study of selumetinib in patients with metastatic biliary cancers. J Clin Oncol 2011;29:2357-63.
18. Hayes DN, Lucas AS, Tanvetyanon T, Krzyzanowska MK, Chung CH, Murphy BA, et al. 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 2012;18:2056-65.
19. Janne PA, Shaw AT, Pereira JR, Jeannin G, Vansteenkiste J, Barrios C, et al. Selumetinib plus docetaxel for KRAS-mutant advanced nonsmall-cell lung cancer: a randomised, multicentre placebo-controlled, phase 2 study. Lancet Oncol 2013;14: 38-47.
20. O'Neil BH, Goff LW, Kauh JS, Strosberg JR, Bekaii-Saab TS, Lee RM, et al. Phase II study of the mitogen-Activated protein kinase 1/2 inhibitor selumetinib in patients with advanced hepatocellular carcinoma. J Clin Oncol 2011;29:2350-6.
21. Staal FJ, Luis TC, Tiemessen MM. WNT signalling in the immune system: WNT is spreading its wings. Nat Rev Immunol 2008;8:581-93.
22. Jessen Jr. Noncanonical Wnt signaling in tumor progression and metastasis. Zebrafish 2009;6:21-8.
23. Wang Y. Wnt/Planar cell polarity signaling: a new paradigm for cancer therapy. Mol Cancer Ther 2009;8:2103-9.
24. Martin SA, Hewish M, Sims D, Lord CJ, Ashworth A. Parallel highthroughput RNA interference screens identify PINK1 as a potential therapeutic target for the treatment of DNA mismatch repair-deficient cancers. Cancer Res 2011;71:1836-48.
25. Mendes-Pereira AM, Sims D, Dexter T, Fenwick K, Assiotis I, Kozarewa I, et al. Genome-wide functional screen identifies a compendium of genes affecting sensitivity to tamoxifen. Proc Natl Acad Sci U S A 2012;109:2730-5.
26. Porter CC, Kim J, Fosmire S, Gearheart CM, van Linden A, Baturin D, et al. Integrated genomic analyses identify WEE1 as a critical mediator of cell fate and a novel therapeutic target in acute myeloid leukemia. Leukemia 2012;26:1266-76.
27. Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A 2005;102:15545-50.
28. Kim J, Tan AC. BiNGS!SL-seq: a bioinformatics pipeline for the analysis and interpretation of deep sequencing genome-wide synthetic lethal screen. Methods Mol Biol 2012;802:389-98.
29. Sullivan KD, Padilla-Just N, Henry RE, Porter CC, Kim J, Tentler JJ, et al. ATM and MET kinases are synthetic lethal with nongenotoxic activation of p53. Nat Chem Biol 2012;8:646-54.
30. Casas-Selves M, Kim J, Zhang Z, Helfrich BA, Gao D, Porter CC, et al. Tankyrase and the canonical Wnt pathway protect lung cancer cells from EGFR inhibition. Cancer Res 2012;72:4154-64.
31. Pitts TM, Tan AC, Kulikowski GN, Tentler JJ, Brown AM, Flanigan SA, et al. Development of an integrated genomic classifier for a novel agent in colorectal cancer: approach to individualized therapy in early development. Clin Cancer Res 2010;16:3193-204.
32. Gregory MA, Phang TL, Neviani P, Alvarez-Calderon F, Eide CA, O'Hare T, et al. Wnt/Ca2+/NFAT signaling maintains survival of Ph+ leukemia cells upon inhibition of Bcr-Abl. Cancer Cell 2010;18:74-87.
33. Davies BR, Logie A, McKay JS, Martin P, Steele S, Jenkins R, et al. 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 2007;6:2209-19.
34. Denton CL, Gustafson DL. Pharmacokinetics and pharmacodynamics of AZD6244 (ARRY-142886) in tumor-bearing nude mice. Cancer Chemother Pharmacol 2011;67:349-60.
35. Morelli MP, Tentler JJ, Kulikowski GN, Tan AC, Bradshaw-Pierce EL, Pitts TM, et al. Preclinical activity of the rational combination of selumetinib (AZD6244) in combination with vorinostat in KRAS-mutant colorectal cancer models. Clin Cancer Res 2012;18:1051-62.
36. Dry JR, Pavey S, Pratilas CA, Harbron C, Runswick S, Hodgson D, et al. Transcriptional pathway signatures predict MEK addiction and response to selumetinib (AZD6244). Cancer Res 2010;70:2264-73.
37. Zhang Y, Yeh JR, Mara A, Ju R, Hines JF, Cirone P, et al. A chemical and genetic approach to the mode of action of fumagillin. Chem Biol 2006;13:1001-9.
38. Illmer T, Schaich M, Platzbecker U, Freiberg-Richter J, Oelschlagel U, von Bonin M, et al. P-glycoprotein-mediated drug efflux is a resistance mechanism of chronic myelogenous leukemia cells to treatment with imatinib mesylate. Leukemia 2004;18:401-8.
39. Horst D, Chen J, Morikawa T, Ogino S, Kirchner T, Shivdasani RA. DifferentialWNT activity in colorectal cancer confers limitedtumorigenic potential and is regulated by MAPK signaling. Cancer Res 2012;72: 1547-56.
40. Kim D, Rath O, Kolch W, Cho KH. A hidden oncogenic positive feedback loop caused by crosstalk between Wnt and ERK pathways. Oncogene 2007;26:4571-9.
41. Wang IC, Snyder J, Zhang Y, Lander J, Nakafuku Y, Lin J, et al. Foxm1 mediates cross talk between Kras/mitogen-Activated protein kinase and canonical Wnt pathways during development of respiratory epithelium. Mol Cell Biol 2012;32:3838-50.
42. Mologni L, Brussolo S, Ceccon M, Gambacorti-Passerini C. Synergistic effects of combined Wnt/KRAS inhibition in colorectal cancer cells. PLoS ONE 2012;7:e51449.
43. Yoon J, Koo KH, Choi KY. MEK1/2 inhibitors AS703026 and AZD6244 may be potential therapies for KRAS mutated colorectal cancer that is resistant to EGFR monoclonal antibody therapy. Cancer Res 2011;71: 445-53.
44. Di Nicolantonio F, Martini M, Molinari F, Sartore-Bianchi A, Arena S, Saletti P, et al. Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer. J Clin Oncol 2008;26:5705-12.
45. Kwak EL, Bang YJ, Camidge DR, ShawAT, Solomon B, Maki RG, et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med 2010;363:1693-703.
46. Lievre A, Bachet JB, Boige V, Cayre A, Le Corre D, Buc E, et al. KRAS mutations as an independent prognostic factor in patients with advanced colorectal cancer treated with cetuximab. J Clin Oncol 2008;26:374-9.
47. Gioeli D, Wunderlich W, Sebolt-Leopold J, Bekiranov S, Wulfkuhle JD, Petricoin EF III, et al. Compensatory pathways induced by MEK inhibition are effective drug targets for combination therapy against castration-resistant prostate cancer. Mol Cancer Ther 2011;10: 1581-90.
48. Shi H, Kong X, Ribas A, Lo RS. Combinatorial treatments that overcome PDGFRbeta-driven resistance of melanoma cells to V600EBRAF inhibition. Cancer Res 2011;71:5067-74.
49. Singh A, Sweeney MF, Yu M, Burger A, Greninger P, Benes C, et al. TAK1 inhibition promotes apoptosis in KRAS-dependent colon cancers. Cell 2012;148:639-50.
50. Jimeno A, Tan AC, Coffa J, Rajeshkumar NV, Kulesza P, Rubio-Viqueira B, et al. Coordinated epidermal growth factor receptor pathway gene overexpression predicts epidermal growth factor receptor inhibitor sensitivity in pancreatic cancer. Cancer Res 2008;68:2841-9.
51. Luo J, Emanuele MJ, Li D, Creighton CJ, Schlabach MR, Westbrook TF, et al. A genome-wide RNAi screen identifies multiple synthetic lethal interactions with the Ras oncogene. Cell 2009;137: 835-48.
52. Whitehurst AW, Bodemann BO, Cardenas J, Ferguson D, Girard L, Peyton M, et al. Synthetic lethal screen identification of chemosensitizer loci in cancer cells. Nature 2007;446:815-9.
53. Pukrop T, Binder C. The complex pathways of Wnt 5a in cancer progression. J Mol Med 2008;86:259-66.
54. Ball DW, Jin N, Rosen DM, Dackiw A, Sidransky D, Xing M, et al. Selective growth inhibition in BRAF mutant thyroid cancer by the mitogen-Activated protein kinase kinase 1/2 inhibitor AZD6244. J Clin Endocrinol Metab 2007;92:4712-8.
55. Haass NK, Sproesser K, Nguyen TK, Contractor R, Medina CA, Nathanson KL, et al. The mitogen-Activated protein/extracellular signal-regulated kinase kinase inhibitor AZD6244 (ARRY-142886) induces growth arrest in melanoma cells and tumor regression when combined with docetaxel. Clin Cancer Res 2008;14:230-9.
56. Holt SV, Logie A, Odedra R, Heier A, Heaton SP, Alferez D, et al. The MEK1/2 inhibitor, selumetinib (AZD6244; ARRY-142886), enhances anti-tumour efficacy when combined with conventional chemotherapeutic agents in human tumour xenograft models. Br J Cancer 2012;106:858-66.
57. Tentler JJ, Tan AC, Weekes CD, Jimeno A, Leong S, Pitts TM, et al. Patient-derived tumour xenografts as models for oncology drug development. Nat Rev Clin Oncol 2012;9:338-50.
58. TCGA. Comprehensive molecular characterization of human colon and rectal cancer. Nature 2012;487:330-7.
59. Hidalgo M, Bruckheimer E, Rajeshkumar NV, Garrido-Laguna I, De Oliveira E, Rubio-Viqueira B, et al. A pilot clinical study of treatment guided by personalized tumorgrafts in patients with advanced cancer. Mol Cancer Ther 2011;10:1311-6.