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mTOR mediates a mechanism of resistance to chemotherapy and defines a rational combination strategy to treat KRAS-mutant lung cancer

Oncogene volume 38, pages 622–636 (2019)Cite this article

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Abstract

Oncogenic KRAS mutations comprise the largest subset of lung cancer defined by genetic alterations, but in the clinic no targeted therapies are available that effectively control mutational KRAS activation. Consequently, patients with KRAS-driven tumors are routinely treated with cytotoxic chemotherapy, which is often transiently effective owing to development of drug resistance. In this study, we show that hyperactivated mammalian target of rapamycin (mTOR) pathway is a characteristic hallmark of KRAS-mutant lung adenocarcinoma after chemotherapy treatment, and that KRAS-mutant lung cancer cells rely on persistent mTOR signaling to resist chemotherapeutic drugs. Coherently, mTOR inhibition circumvents the refractory phenotype and restores sensitivity of resistant KRAS-mutant lung cancer cells to chemotherapy. Importantly, drug combinations of clinically approved mTOR inhibitors and chemotherapy drugs synergize in inhibiting cell proliferation of KRAS-mutant cancer cells in vitro and in vivo, and the efficacy of this combination treatment correlates with the magnitude of mTOR activity induced by chemotherapy alone. These results pinpoint mTOR as a mechanism of resistance to chemotherapy in KRAS-mutant lung cancer and validate a rational and readily translatable strategy that combines mTOR inhibitors with standard chemotherapy to treat KRAS-mutant adenocarcinoma, the most common and deadliest lung cancer subset.

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Acknowledgements

We gratefully acknowledge Lung Cancer Center (LCC), Bern University Hospital and the Tissue Bank Bern (TBB), Institute of Pathology, University of Bern, in acquiring patient tissues. We thank Silvia Suardi and José Galván (Institute of Pathology) and Colin Tièche and Ming Qiao (Division of General Thoracic Surgery) for technical assistance and help with data acquisition and analysis, Dr. med. Michael von Gunten (Pathologie Länggasse, Bern, Switzerland) and Dr. med. Mathias Gugger (Promed SA Laboratoire médical, Freiburg, Switzerland) for providing pre-chemotherapy biopsies, professor Marianne Geiser (Institute of Anatomy, University of Bern, Bern, Switzerland) and Dr. Yitzhak Zimmer (Department of Radiation Oncology, Bern University Hospital, Bern, Switzerland) for cell lines. This work was supported by Swiss Cancer League (#KFS-3772-08-2015; to R.-W. Peng), Cancer League of the Canton of Bern (to R-W. Peng), a PhD fellowship from China Scholarship Council (to S.-Q. Liang) and a MD-PhD fellowship from Swiss Cancer League (to E.D. Bührer).

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Authors and Affiliations

  1. Division of General Thoracic Surgery, Inselspital, Bern University Hospital, Bern, Switzerland

    Shun-Qing Liang, Thomas M. Marti, Duo Xu, Laurène Froment, Haitang Yang, Sean R. R. Hall, Zhang Yang, Gregor J. Kocher, Ralph A. Schmid & Ren-Wang Peng

  2. Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland

    Shun-Qing Liang, Thomas M. Marti, Duo Xu, Laurène Froment, Haitang Yang, Sean R. R. Hall, Zhang Yang, Gregor J. Kocher, Ralph A. Schmid & Ren-Wang Peng

  3. Tumor Immunology, Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland

    Elias D. Bührer, Michael A. Amrein, Carsten Riether & Adrian F. Ochsenbein

  4. Institute of Pathology, University of Bern, Bern, Switzerland

    Sabina Berezowska & Erik Vassella

  5. Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland

    Duo Xu, Haitang Yang & Zhang Yang

  6. Department of Medical Oncology, Inselspital, Bern University Hospital, Bern, Switzerland

    Carsten Riether & Adrian F. Ochsenbein

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Liang, SQ., Bührer, E.D., Berezowska, S. et al. mTOR mediates a mechanism of resistance to chemotherapy and defines a rational combination strategy to treat KRAS-mutant lung cancer. Oncogene 38, 622–636 (2019). https://doi.org/10.1038/s41388-018-0479-6

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