2. Academic Validation
  3. 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. doi: 10.18632/oncotarget.26129.
Dennis Ruder 1 2,  Vassiliki Papadimitrakopoulou 3,  Kazuhiko Shien 2,  Carmen Behrens 3,  Neda Kalhor 4,  Huiqin Chen 5,  Li Shen 6,  J Jack Lee 5,  Waun Ki Hong 3,  Ximing Tang 2,  Luc Girard 7,  John D Minna 7,  Lixia Diao 6,  Jing Wang 6,  Barbara Mino 2,  Pamela Villalobos 2,  Jaime Rodriguez-Canales 2,  Nana E Hanson 2,  James Sun 8,  Vincent Miller 8,  Joel Greenbowe 8,  Garrett Frampton 8,  Roy S Herbst 9,  Veera Baladandayuthapani 5,  Ignacio I Wistuba 2,  Julie G Izzo 2
Affiliations

Affiliations

  • 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.
PMID: 30338041 DOI: 10.18632/oncotarget.26129
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.

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