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

• Published in: Oncogene 2019-01, Vol.38 (5), p.622-636
• Main Authors: Liang, Shun-Qing, Bührer, Elias D., Berezowska, Sabina, Marti, Thomas M., Xu, Duo, Froment, Laurène, Yang, Haitang, Hall, Sean R. R., Vassella, Erik, Yang, Zhang, Kocher, Gregor J., Amrein, Michael A., Riether, Carsten, Ochsenbein, Adrian F., Schmid, Ralph A., Peng, Ren-Wang
• Format: Article
• Language: English
• Subjects: 13; 13/89; 38; 45; 631/67/1612/1350; 64; 692/53/2423; 82; 96; Adenocarcinoma; Adenocarcinoma of Lung - drug therapy; Adenocarcinoma of Lung - enzymology; Adenocarcinoma of Lung - genetics; Adenocarcinoma of Lung - pathology; Animals; Apoptosis; B cells; Cancer cells; Cancer therapies; Cancer treatment; Care and treatment; Cell Biology; Cell proliferation; Chemotherapy; Combination drug therapy; Cytotoxicity; Development and progression; Drug approval; Drug resistance; Drug Resistance, Neoplasm; Gene mutation; Genetic aspects; Health aspects; Human Genetics; Humans; Internal Medicine; K-Ras protein; Lung cancer; Lung Neoplasms - drug therapy; Lung Neoplasms - enzymology; Lung Neoplasms - genetics; Lung Neoplasms - pathology; Medicine; Medicine & Public Health; Mice; Mice, Knockout; Oncogenes; Oncology; Phenotypes; Phosphotransferases; Proto-Oncogene Proteins p21(ras) - genetics; Proto-Oncogene Proteins p21(ras) - metabolism; Rapamycin; Synergism; TOR protein; TOR Serine-Threonine Kinases - genetics; TOR Serine-Threonine Kinases - metabolism; Tumors
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/s41388-018-0479-6

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.