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Oncotarget. 2018 Sep 21;9(74):33995-34008. doi: 10.18632/oncotarget.26129. eCollection 2018 Sep 21.

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

Author information

1
Graduate Program in Human and Molecular Genetics and Cancer Biology, MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, Texas, USA.
2
Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
3
Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
4
Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
5
Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
6
Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
7
Hamon Center for Therapeutic Oncology Research, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.
8
Foundation Medicine, Inc., Cambridge, Massachusetts, USA.
9
Yale Cancer Center, Yale School of Medicine, New Haven, Connecticut, USA.

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 study provides evidence of a distinctive therapeutic opportunity in a subset of NSCLC carrying concomitant RICTOR/KRAS alterations.

KEYWORDS:

KRAS mutation; MAPK pathway; RICTOR gene abnormalities; mTORC2; non-small cell lung cancer

Conflict of interest statement

CONFLICTS OF INTEREST No relationship to disclose. Potential conflicts of interest: J.S., G.M.F., J.G., and V.M. are employees of and shareholders in Foundation Medicine.

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