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
| Autor: | Catherine A. O’Brien, Mark J. Sinnamon, Eric S. Martin, Nicole E. Baryla, Ping Jiang, Kenneth E. Hung, Julie L.C. Kan, Scott L. Weinrich, Bradly G. Wouters, Oivin Guicherit, Valeria Fantin, David Shields, Peter Olson, Trevor D. McKee, Nathan V. Lee, James G. Christensen, Tao Xie, Paul A. Rejto, Jatin Roper, Jason Isaacson, Todd VanArsdale, Peter J. Belmont |
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| Rok vydání: | 2014 |
| Předmět: |
Transcription
Genetic Cell Survival Cell Separation Mice SCID Pharmacology medicine.disease_cause Biochemistry chemistry.chemical_compound Mice ErbB Cell Line Tumor medicine Animals Humans ERBB3 Enzyme Inhibitors Phosphorylation neoplasms Molecular Biology Mechanistic target of rapamycin PI3K/AKT/mTOR pathway beta Catenin EGFR inhibitors Cell Proliferation Phosphoinositide-3 Kinase Inhibitors biology TOR Serine-Threonine Kinases Cell Biology Flow Cytometry Dacomitinib ErbB Receptors Disease Models Animal Genes ras chemistry Drug Resistance Neoplasm Mutation biology.protein ras Proteins Cyclin-dependent kinase 8 Female KRAS Tumor Suppressor Protein p53 Colorectal Neoplasms Genetic Engineering Neoplasm Transplantation Signal Transduction |
| Zdroj: | Science signaling. 7(351) |
| ISSN: | 1937-9145 |
| Popis: | 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 mechanisms to PI3K/mTOR inhibition in KRAS-mutant CRC. Using genetically engineered mouse model cells that had acquired resistance to the dual PI3K/mTOR small-molecule inhibitor PF-04691502, we determined with chemical library screens that inhibitors of the ERBB [epidermal growth factor receptor (EGFR)] family restored the sensitivity to PF-04691502. Although EGFR inhibitors alone have limited efficacy in reducing KRAS-mutant tumors, we found that PF-04691502 induced the abundance, phosphorylation, and activity of EGFR, ERBB2, and ERBB3 through activation of FOXO3a (forkhead box O 3a), a transcription factor inhibited by the PI3K to AKT pathway. PF-04691502 also induced a stem cell-like gene expression signature. KRAS-mutant patient-derived xenografts from mice treated with PF-04691502 had a similar gene expression signature and exhibited increased EGFR activation, suggesting that this drug-induced resistance mechanism may occur in patients. Combination therapy with dacomitinib (a pan-ERBB inhibitor) restored sensitivity to PF-04691502 in drug-resistant cells in culture and induced tumor regression in drug-resistant allografts in mice. Our findings suggest that combining PI3K/mTOR and EGFR inhibitors may improve therapeutic outcome in patients with KRAS-mutant CRC. |
| Databáze: | OpenAIRE |
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