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

Dennis Ruder, Vassiliki 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 MillerJoel Greenbowe, Garrett Frampton, Roy S. Herbst, Veera Baladandayuthapani, Ignacio I. Wistuba, Julie G. Izzo

Research output: Contribution to journalArticle

4 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)33995-34008
Number of pages14
JournalOncotarget
Volume9
Issue number74
Publication statusPublished - Sep 1 2018

Keywords

  • KRAS mutation
  • MAPK pathway
  • MTORC2
  • Non-small cell lung cancer
  • RICTOR gene abnormalities

ASJC Scopus subject areas

  • Oncology

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  • Cite this

    Ruder, D., Papadimitrakopoulou, V., Shien, K., Behrens, C., Kalhor, N., Chen, H., Shen, L., Jack Lee, J., Hong, W. K., Tang, X., Girard, L., Minna, J. D., Diao, L., Wang, J., Mino, B., Villalobos, P., Rodriguez-Canales, J., Hanson, N. E., Sun, J., ... Izzo, J. G. (2018). Concomitant targeting of the mTOR/MAPK pathways: Novel therapeutic strategy in subsets of RICTOR/KRAS-altered non-small cell lung cancer. Oncotarget, 9(74), 33995-34008.