| Autor: |
Dennis, Ruder, Vassiliki, Papadimitrakopoulou, Kazuhiko, Shien, Carmen, Behrens, Neda, Kalhor, Huiqin, Chen, Li, Shen, J Jack, Lee, Waun Ki, Hong, Ximing, Tang, Luc, Girard, John D, Minna, Lixia, Diao, Jing, Wang, Barbara, Mino, Pamela, Villalobos, Jaime, Rodriguez-Canales, Nana E, Hanson, James, Sun, Vincent, Miller, Joel, Greenbowe, Garrett, Frampton, Roy S, Herbst, Veera, Baladandayuthapani, Ignacio I, Wistuba, Julie G, Izzo |
| Rok vydání: |
2018 |
| Předmět: |
|
| Zdroj: |
Oncotarget |
| ISSN: |
1949-2553 |
| Popis: |
Despite a therapeutic paradigm shift into targeted-driven medicinal approaches, resistance to therapy remains a hallmark of lung cancer, driven by biological and molecular diversity. Using genomic and expression data from advanced non-small cell lung cancer (NSCLC) patients enrolled in the BATTLE-2 clinical trial, we identified RICTOR alterations in a subset of lung adenocarcinomas and found RICTOR expression to carry worse overall survival. RICTOR-altered cohort was significantly enriched in KRAS/MAPK axis mutations, suggesting a co-oncogenic driver role in these molecular settings. Using NSCLC cell lines, we showed that, distinctly in KRAS mutant backgrounds, RICTOR blockade impairs malignant properties and generates a compensatory enhanced activation of the MAPK pathway, exposing a unique therapeutic vulnerability. In vitro and in vivo concomitant pharmacologic inhibition of mTORC1/2 and MEK1/2 resulted in synergistic responses of anti-tumor effects. Our study provides evidence of a distinctive therapeutic opportunity in a subset of NSCLC carrying concomitant RICTOR/KRAS alterations. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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