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

2018; Impact Journals LLC; Volume: 9; Issue: 74 Linguagem: Inglês

10.18632/oncotarget.26129

1949-2553

Dennis Ruder, Vassiliki A. 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 A. Miller, Joel Greenbowe, Garrett M. Frampton, Roy S. Herbst, Veera Baladandayuthapani, Ignacio I. Wistuba, Julie Izzo,

Protein Tyrosine Phosphatases

// Dennis Ruder 1, 2 , Vassiliki Papadimitrakopoulou 4 , Kazuhiko Shien 2 , Carmen Behrens 4 , Neda Kalhor 5 , Huiqin Chen 6 , Li Shen 3 , J. Jack Lee 6 , Waun Ki Hong 4 , Ximing Tang 2 , Luc Girard 7 , John D. Minna 7 , Lixia Diao 3 , Jing Wang 3 , Barbara Mino 2 , Pamela Villalobos 2 , Jaime Rodriguez-Canales 2 , Nana E. Hanson 2 , James Sun 9 , Vincent Miller 9 , Joel Greenbowe 9 , Garrett Frampton 9 , Roy S. Herbst 8 , Veera Baladandayuthapani 6 , Ignacio I. Wistuba 2 and Julie G. Izzo 2 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 Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA 4 Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA 5 Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA 6 Department of Biostatistics, 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 Yale Cancer Center, Yale School of Medicine, New Haven, Connecticut, USA 9 Foundation Medicine, Inc., Cambridge, Massachusetts, USA Correspondence to: Julie G. Izzo, email: jizzo@mdanderson.org Ignacio I. Wistuba, email: iiwistuba@mdanderson.org 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 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.