TY - JOUR
T1 - Concomitant targeting of the mTOR/MAPK pathways
T2 - Novel therapeutic strategy in subsets of RICTOR/KRAS-altered non-small cell lung cancer
AU - Ruder, Dennis
AU - Papadimitrakopoulou, Vassiliki
AU - Shien, Kazuhiko
AU - Behrens, Carmen
AU - Kalhor, Neda
AU - Chen, Huiqin
AU - Shen, Li
AU - Jack Lee, J.
AU - Hong, Waun Ki
AU - Tang, Ximing
AU - Girard, Luc
AU - Minna, John D.
AU - Diao, Lixia
AU - Wang, Jing
AU - Mino, Barbara
AU - Villalobos, Pamela
AU - Rodriguez-Canales, Jaime
AU - Hanson, Nana E.
AU - Sun, James
AU - Miller, Vincent
AU - Greenbowe, Joel
AU - Frampton, Garrett
AU - Herbst, Roy S.
AU - Baladandayuthapani, Veera
AU - Wistuba, Ignacio I.
AU - Izzo, Julie G.
N1 - Funding Information:
This study was supported in part by grants R01CA155196-01A1, The University of Texas Lung Specialized Programs of Research Excellence grant P50CA70907, and P30CA01667 (Cancer Center Core Grant) from the National Cancer Institute.
Publisher Copyright:
Copyright: Ruder et al.
PY - 2018/9/1
Y1 - 2018/9/1
N2 - 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.
AB - 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.
KW - KRAS mutation
KW - MAPK pathway
KW - MTORC2
KW - Non-small cell lung cancer
KW - RICTOR gene abnormalities
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M3 - Article
AN - SCOPUS:85053815762
SN - 1949-2553
VL - 9
SP - 33995
EP - 34008
JO - Oncotarget
JF - Oncotarget
IS - 74
ER -
