Concomitant targeting of the mTOR/MAPK pathways: novel therapeutic strategy in subsets of RICTOR/KRAS-altered non-small cell lung cancer.

Concomitant targeting of the mTOR/MAPK pathways: novel therapeutic strategy in subsets of RICTOR/KRAS-altered non-small cell lung cancer. Oncotarget. 2018 Sep 21;9(74):33995-34008 Authors: Ruder D, Papadimitrakopoulou V, Shien K, Behrens C, Kalhor N, Chen H, Shen L, Lee JJ, Hong WK, Tang X, Girard L, Minna JD, Diao L, Wang J, Mino B, Villalobos P, Rodriguez-Canales J, Hanson NE, Sun J, Miller V, Greenbowe J, Frampton G, Herbst RS, Baladandayuthapani V, Wistuba II, Izzo JG Abstract 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...
Source: Oncotarget - Category: Cancer & Oncology Tags: Oncotarget Source Type: research