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Resistance to PI3K/mTOR inhibitor PF-04691502 in KRAS mutant colorectal cancer models reveals a sensitivity to combination with EGFR inhibition

ABSTRACT: We explored potential bypass mechanisms to PI3K/mTOR-directed therapy in KRAS mutant CRC models, utilizing genetically engineered mouse models (GEMM) to generate acquired resistance to the targeted dual PI3K/mTOR small molecule inhibitor PF-04691502. Transcriptomic analysis revealed a dynamic stem-like progenitor signature which was increased in the presence of drug pressure.

INSTRUMENT(S): Illumina HiSeq 2000

ORGANISM(S): Mus musculus

SUBMITTER: Tao Xie

PROVIDER: E-MTAB-2510 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Resistance to dual blockade of the kinases PI3K and mTOR in KRAS-mutant colorectal cancer models results in combined sensitivity to inhibition of the receptor tyrosine kinase EGFR.

Belmont Peter J PJ Jiang Ping P McKee Trevor D TD Xie Tao T Isaacson Jason J Baryla Nicole E NE Roper Jatin J Sinnamon Mark J MJ Lee Nathan V NV Kan Julie L C JL Guicherit Oivin O Wouters Bradly G BG O'Brien Catherine A CA Shields David D Olson Peter P VanArsdale Todd T Weinrich Scott L SL Rejto Paul P Christensen James G JG Fantin Valeria R VR Hung Kenneth E KE Martin Eric S ES

Science signaling 20141111 351

Targeted blockade of aberrantly activated signaling pathways is an attractive therapeutic strategy for solid tumors, but drug resistance is common. KRAS is a frequently mutated gene in human cancer but remains a challenging clinical target. Inhibitors against KRAS signaling mediators, namely, PI3K (phosphatidylinositol 3-kinase) and mTOR (mechanistic target of rapamycin), have limited clinical efficacy as single agents in KRAS-mutant colorectal cancer (CRC). We investigated potential bypass mech ...[more]

PMID: 25389372

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Comparative study of a mTOR inhibitor, a pan-PI3K inhibitor and a dual PI3K/mTOR inhibitor in MCL

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Combined PI3K/mTOR and MEK Inhibition Provides Broad Anti-Tumor Activity in Faithful Murine Cancer Models

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2023-08-23 | PXD043239 | Pride

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2016-12-01 | E-MTAB-5286 | biostudies-arrayexpress

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