Modeling targeted inhibition of MEK and PI3 kinase in human pancreatic cancer

Molecular Cancer Therapeutics

Volumn 14, Issue 1, 2015, Pages 40-47

  Junttila, Melissa R ^a   Devasthali, Vidusha ^a   Cheng, Jason H ^a   Castillo, Joseph ^a   Metcalfe, Ciara ^a   Clermont, Anne C ^a   Otter, Douglas Den ^a   Chan, Emily ^a   Bou Reslan, Hani ^a   Cao, Tim ^a   Forrest, William ^a   Nannini, Michelle A ^a   French, Dorothy ^a   Carano, Richard ^a   Merchant, Mark ^a   Hoeflich, Klaus P ^a   Singh, Mallika ^a,b  

^a GENENTECH INC   (United States)

^b Patronus Therapeutics   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

COBIMETINIB; GEMCITABINE; MITOGEN ACTIVATED PROTEIN KINASE; PHOSPHATIDYLINOSITOL 3 KINASE; PICTILISIB; PROTEIN KINASE B; 2-(1H-INDAZOL-4-YL)-6-(4-METHANESULFONYLPIPERAZIN-1-YLMETHYL)-4-MORPHOLIN-4-YLTHIENO(3,2-D)PYRIMIDINE; ANTINEOPLASTIC AGENT; AZETIDINE DERIVATIVE; DEOXYCYTIDINE; GDC-0973; INDAZOLE DERIVATIVE; KRAS2 PROTEIN, MOUSE; MITOGEN ACTIVATED PROTEIN KINASE KINASE 1; PIPERIDINE DERIVATIVE; PROTEIN KINASE INHIBITOR; PROTEIN P21; SULFONAMIDE;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; CANCER COMBINATION CHEMOTHERAPY; CANCER INHIBITION; CANCER SIZE; CANCER SURVIVAL; CONTROLLED STUDY; ENZYME INHIBITION; ENZYME PHOSPHORYLATION; FEMALE; GENETICALLY ENGINEERED MOUSE STRAIN; IMMUNOHISTOCHEMISTRY; MALE; MOUSE; MULTIPLE CYCLE TREATMENT; NONHUMAN; ONCOGENE K RAS; OVERALL SURVIVAL; PANCREAS ADENOCARCINOMA; PRIORITY JOURNAL; SIGNAL TRANSDUCTION; UPREGULATION; WESTERN BLOTTING; ANALOGS AND DERIVATIVES; ANIMAL; ANTAGONISTS AND INHIBITORS; BIOLOGICAL MODEL; CARCINOMA, PANCREATIC DUCTAL; DOSE RESPONSE; DRUG SCREENING; GENETICS; HEALTH CARE QUALITY; HUMAN; MUTATION; PANCREATIC NEOPLASMS; PATHOLOGY; TUMOR CELL LINE;

ANIMALS; ANTINEOPLASTIC COMBINED CHEMOTHERAPY PROTOCOLS; AZETIDINES; CARCINOMA, PANCREATIC DUCTAL; CELL LINE, TUMOR; DEOXYCYTIDINE; DOSE-RESPONSE RELATIONSHIP, DRUG; HUMANS; INDAZOLES; MAP KINASE KINASE 1; MICE; MODELS, BIOLOGICAL; MUTATION; PANCREATIC NEOPLASMS; PHOSPHATIDYLINOSITOL 3-KINASES; PIPERIDINES; PROTEIN KINASE INHIBITORS; PROTO-ONCOGENE PROTEINS P21(RAS); STANDARD OF CARE; SULFONAMIDES; XENOGRAFT MODEL ANTITUMOR ASSAYS;

EID: 84921296898     PISSN: 15357163     EISSN: 15388514     Source Type: Journal    
DOI: 10.1158/1535-7163.MCT-14-0030     Document Type: Article

References (30)

1. American Cancer Society Cancer facts & figures [Internet]; 2013 [cited 2013 Dec 18]. Available from: http://www.cancer.org/research/cancerfactsfigures/cancerfactsfigures/cancer-facts-figures-2013.
2. Hoff Von DD, Ramanathan RK, Borad MJ, Laheru DA, Smith LS, Wood TE, et al. Gemcitabine plus nab-paclitaxel is an active regimen in patients with advanced pancreatic cancer: a phase I/II trial. J Clin Oncol 2011;29:4548-54.
3. Jones S, Zhang X, Parsons DW, Lin JC-H, Leary RJ, Angenendt P, et al. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science 2008;321:1801-6.
4. Biankin AV, Waddell N, Kassahn KS, Gingras M-C, Muthuswamy LB, Johns AL, et al. Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes. Nature 2012;491:399-405.
5. Baines AT, Xu D, Der CJ. Inhibition of Ras for cancer treatment: the search continues. Future Med Chem 2011;3:1787-808.
6. Chen Z, Cheng K, Walton Z, Wang Y, Ebi H, Shimamura T, et al. A murine lung cancer co-clinical trial identifies genetic modifiers of therapeutic response. Nature 2012;483:613-7.
7. Jänne PA, Shaw AT, Pereira JR, Jeannin G, Vansteenkiste J, Barrios C, et al. Selumetinib plus docetaxel for KRAS-mutant advanced non-small-cell lung cancer: a randomised, multicentre, placebo-controlled, phase 2 study. Lancet Oncol 2013;14:38-47.
8. McCubrey JA, Steelman LS, Chappell WH, Abrams SL, Franklin RA, Montalto G, et al. Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR cascade inhibitors: howmutations can result in therapy resistance and how to overcome resistance. Oncotarget 2012;3:1068-111.
9. Courtney KD, Corcoran RB, Engelman JA. The PI3K pathway as drug target in human cancer. J Clin Oncol 2010;28:1075-83.
10. Engelman JA, Chen L, Tan X, Crosby K, Guimaraes AR, Upadhyay R, et al. Effective use of PI3K and MEK inhibitors to treat mutant Kras G12D and PIK3CA H1047R murine lung cancers. Nat Med 2008;14:1351-6.
11. Kola I, Landis J. Can the pharmaceutical industry reduce attrition rates? Nat Rev Drug Discov 2004;3:711-5.
12. Singh M, Murriel CL, Johnson L. Genetically engineered mouse models: closing the gap between preclinical data and trial outcomes. Cancer Res 2012;72:2695-700.
13. Van Dyke T. Finding the tumor copycat: approximating a human cancer. Nat Med 2010;16:976-7.
14. Singh M, Lima A, Molina R, Hamilton P, Clermont AC, Devasthali V, et al. Assessing therapeutic responses in Kras mutant cancers using genetically engineered mouse models. Nat Biotechnol 2010;28:585-93.
15. Pinheiro J, Bates D, DebRoy S, et al. nlme: linear and nonlinear mixed effects models. R package. Available from: http://CRAN.R-project.org/package=nlme.
16. R Core Team (2013). R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. Available from: http://www.R-project.org/.
17. Hoeflich KP, Merchant M, Orr C, Chan J, Otter Den D, Berry L, et al. Intermittent administration of MEK inhibitor GDC-0973 plus PI3K inhibitor GDC-0941 triggers robust apoptosis and tumor growth inhibition. Cancer Res 2012;72:210-9.
18. Folkes AJ, Ahmadi K, Alderton WK, Alix S, Baker SJ, Box G, et al. The identification of 2-(1H-indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (GDC-0941) as a potent, selective, orally bioavailable inhibitor of class I PI3 kinase for the treatment of cancer. J Med Chem 2008;51:5522-32.
19. Eser S, Reiff N, Messer M, Seidler B, Gottschalk K, Dobler M, et al. Selective requirement of PI3K/PDK1 signaling for kras oncogene-driven pancreatic cell plasticity and cancer. Cancer Cell 2013;23:406-20.
20. LoRusso P, Shapiro G, Pandya SS, Kwak EL, Jones C, Belvin M, et al. A first-in-human phase Ib study to evaluate the MEK inhibitor GDC-0973, combined with the pan-PI3K inhibitor GDC-0941, in patients with advanced solid tumors. J Clin Oncol 2012;30:(suppl; abstr 2566).
21. Phan VT, Wu X, Cheng JH, Sheng RX, Chung AS, Zhuang G, et al. Oncogenic RAS pathway activation promotes resistance to anti-VEGF therapy through G-CSF-induced neutrophil recruitment. Proc Natl Acad Sci U S A 2013;110:6079-84.
22. Collisson EA, Trejo CL, Silva JM, Gu S, Korkola JE, Heiser LM, et al. A central role for RAF→MEK→ERK signaling in the genesis of pancreatic ductal adenocarcinoma. Cancer Discov 2012;2:685-93.
23. Singh A, Greninger P, Rhodes D, Koopman L, Violette S, Bardeesy N, et al. A gene expression signature associated with "K-Ras addiction" reveals regulators of EMT and tumor cell survival. Cancer Cell 2009;15:489-500.
24. De Luca A, Maiello MR, D'Alessio A, Pergameno M, Normanno N. The RAS/RAF/MEK/ERK and the PI3K/AKT signalling pathways: role in cancer pathogenesis and implications for therapeutic approaches. Expert Opin Ther Targets 2012;16:S17-27.
25. Ying H, Kimmelman AC, Lyssiotis CA, Hua S, Chu GC, Fletcher-Sananikone E, et al. Oncogenic Kras maintains pancreatic tumors through regulation of anabolic glucose metabolism. Cell 2012;149:656-70.
26. Son J, Lyssiotis CA, Ying H, Wang X, Hua S, Ligorio M, et al. Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway. Nature 2013;496:101-5.
27. Mathijssen RHJ, Sparreboom A, Verweij J. Determining the optimal dose in the development of anticancer agents. Nat Rev Clin Oncol 2014;11:272-81.
28. Infante JR, Somer BG, Park JO, Li C-P, Scheulen ME, Kasubhai SM, et al. A randomized, double-blind, placebo-controlled trial of trametinib, a MEK inhibitor, in combination with gemcitabine for patients with untreated metastatic adenocarcinoma of the pancreas. Eur J Cancer 2014;50:2072-81.
29. Hatzivassiliou G, Haling JR, Chen H, Song K, Price S, Heald R, et al. Mechanism ofMEK inhibition determines efficacy in mutant KRAS- versus BRAF-driven cancers. Nature 2013;501:232-6.
30. Lito P, Saborowski A, Yue J, SolomonM, Joseph E, Gadal S, et al. Disruption of CRAF-mediated MEK activation is required for effective MEK inhibition in KRAS mutant tumors. Cancer Cell 2014;25:697-710.