39 - Freie Mitteilung
Clinical works I
16. Mai 2019, 08:30 - 10:00, Bellavista 2, 6. OG
A novel combination strategy to treat KRAS-mutant lung cancer
R.-W. Peng, S.-Q. Liang, E. D. Bührer, S. Berezowska, T. M. Marti, L. Froment, H. Yang, S. R. Hall, E. Vassella, Z. Yang, G. J. Kocher, M. J. Amrein, C. Riether, A. F. Ochsenbein, R. A. Schmid, Presenter: D. Xu (Bern)
Drug resistance inevitably limits clinical efficacy of cancer treatment, which is particularly relevant for KRAS-mutant cancers, the most common type of human malignancies defined by genetic alterations and the largest subset of tumors that cannot be effectively targeted by currently available therapeutics. The purpose of this study is to identify novel drug targets whose inhibition enhances the antitumor efficacy of standard first-line chemotherapy.
Various in vitro models that recapitulate KRAS-mutant lung cancer cells evolving acquired resistance to chemotherapy (cisplatin/pemetrexed) were generated and subjected to pharmacological screens. Tumor vulnerabilities selectively associated with drug-resistant cells were identified and characterized by in vitro, ex vivo and in vivo approaches.
We found that the mammalian target of rapamycin (mTOR) pathway is hyperactivated in KRAS-mutant lung cancer cells that evolve resistance to chemotherapy and in patient-derived KRAS-mutant lung adenocarcinoma treated with chemotherapy. We further showed that drug-resistant KRAS-mutant lung cancer cells rely on persistent mTOR signaling for survival and that its inhibition restores sensitivity of resistant KRAS-mutant lung cancer cells to chemotherapy. Importantly, drug combinations of clinically approved mTOR inhibitors with chemotherapy synergize in inhibiting cell proliferation of KRAS-mutant cancer cells in vitro and in vivo. These results pinpoint activated mTOR signaling as a mechanism of resistance to chemotherapy in KRAS-mutant lung cancer and validate a rational and readily translatable strategy to treat KRAS-mutant lung cancer.
Our study identifies a novel mechanism of resistance mechansim to chemotherapy and validates a combination strategy to treat KRAS-mutant lung cancer.