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
  • 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.
Products