Pharmacological Induction of RAS-GTP Confers RAF Inhibitor Sensitivity in KRAS Mutant Tumors
| Autor: | Joachim Rudolph, Thomas Hunsaker, Christiaan Klijn, Christine Orr, Matthew R. Durk, Scott E. Martin, Dhara N. Amin, Mark Merchant, Frances Shanahan, Yihong Yu, Richard M. Neve, Xiaolin Zhang, Amy Gustafson, John Chan, Shiva Malek, Hank La, Eva Lin, Avinashnarayan Venkatanarayan, Ivana Yen, Scott A. Foster |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
MAPK/ERK pathway Proto-Oncogene Proteins B-raf Cancer Research GTP' Mutant medicine.disease_cause Proto-Oncogene Proteins p21(ras) 03 medical and health sciences Phosphatidylinositol 3-Kinases Cell Line Tumor medicine Humans Protein Kinase Inhibitors PI3K/AKT/mTOR pathway Chemistry MEK inhibitor Cell Biology 030104 developmental biology Oncology Cell culture Mutation Cancer research ras Proteins Phosphorylation KRAS Guanosine Triphosphate |
| Zdroj: | Cancer cell. 34(4) |
| ISSN: | 1878-3686 |
| Popis: | Targeting KRAS mutant tumors through inhibition of individual downstream pathways has had limited clinical success. Here we report that RAF inhibitors exhibit little efficacy in KRAS mutant tumors. In combination drug screens, MEK and PI3K inhibitors synergized with pan-RAF inhibitors through an RAS-GTP-dependent mechanism. Broad cell line profiling with RAF/MEK inhibitor combinations revealed synergistic efficacy in KRAS mutant and wild-type tumors, with KRASG13D mutants exhibiting greater synergy versus KRASG12 mutant tumors. Mechanistic studies demonstrate that MEK inhibition induced RAS-GTP levels, RAF dimerization and RAF kinase activity resulting in MEK phosphorylation in synergistic tumor lines regardless of KRAS status. Taken together, our studies uncover a strategy to rewire KRAS mutant tumors to confer sensitivity to RAF kinase inhibition. |
| Databáze: | OpenAIRE |
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