Concomitant targeting of the mTOR/MAPK pathways: novel therapeutic strategy in subsets of RICTOR/KRAS-altered non-small cell lung cancer
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Dennis Ruder1,2, Vassiliki Papadimitrakopoulou4, Kazuhiko Shien2, Carmen Behrens4, Neda Kalhor5, Huiqin Chen6, Li Shen3, J. Jack Lee6, Waun Ki Hong4, Ximing Tang2, Luc Girard7, John D. Minna7, Lixia Diao3, Jing Wang3, Barbara Mino2, Pamela Villalobos2, Jaime Rodriguez-Canales2, Nana E. Hanson2, James Sun9, Vincent Miller9, Joel Greenbowe9, Garrett Frampton9, Roy S. Herbst8, Veera Baladandayuthapani6, Ignacio I. Wistuba2 and Julie G. Izzo2
1Graduate Program in Human and Molecular Genetics and Cancer Biology, MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, Texas, USA
2Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
3Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
4Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
5Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
6Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
7Hamon Center for Therapeutic Oncology Research, The University of Texas Southwestern Medical Center, Dallas, Texas, USA
8Yale Cancer Center, Yale School of Medicine, New Haven, Connecticut, USA
9Foundation Medicine, Inc., Cambridge, Massachusetts, USA
Julie G. Izzo, email: firstname.lastname@example.org
Ignacio I. Wistuba, email: email@example.com
Keywords: RICTOR gene abnormalities; KRAS mutation; MAPK pathway; mTORC2; non-small cell lung cancer
Received: April 13, 2018 Accepted: September 09, 2018 Published: September 21, 2018
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.
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