mTOR mediates a mechanism of resistance to chemotherapy and defines a rational combination strategy to treat KRAS-mutant lung cancer
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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Combined clinically approved mTOR inhibitor and chemotherapy showed strong synergism in inhibiting proliferation of cancer cells harboring KRAS mutation specifically.
“Combined clinically approved mTOR inhibitor and chemotherapy showed a strong synergism in inhibiting proliferation of cancer cells harboring KRAS-mutation specifically.”
From New Horizons in KRAS-Mutant Lung Cancer: Dawn After Darkness (2019) · cites this paper as [84]
Hyperactivated mTOR signaling was observed exclusively in lung cancer patient samples with KRAS mutations but not in those carrying wild-type KRAS.
“We observed exclusively hyperactivated mTOR signaling in lung cancer patient samples with KRAS-mutations but not in those carrying wild-type KRAS.”
From New Horizons in KRAS-Mutant Lung Cancer: Dawn After Darkness (2019) · cites this paper as [84]
The efficacy of combined mTOR inhibitor and chemotherapy correlates with the magnitude of mTOR activity induced by chemotherapy alone.
“Additionally, the efficacy of this combination treatment correlates with the magnitude of mTOR activity induced by chemotherapy alone.”
From New Horizons in KRAS-Mutant Lung Cancer: Dawn After Darkness (2019) · cites this paper as [84]
Activation of mTOR signaling mediates a key resistance mechanism to chemotherapy in KRAS-mutant lung cancer.
“We recently found that activation of mTOR signaling mediates a key resistance mechanism to chemotherapy in KRAS-mutant lung cancer (84).”
From New Horizons in KRAS-Mutant Lung Cancer: Dawn After Darkness (2019) · cites this paper as [84]
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New Horizons in KRAS-Mutant Lung Cancer: Dawn After Darkness
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- Authors
- Liang, S.-Q., Bührer, E. D., Berezowska, S., Marti, T. M., Xu, D., Froment, L., Yang, H., Hall, S. R. R., Vassella, E., Yang, Z., Kocher, G. J., Amrein, M. A., Riether, C., Ochsenbein, A. F., Schmid, R. A., & Peng, R.-W.
- Affiliations
- University of Bern (CH)
- Corresponding author
- Schmid, Ralph A.
- Peng, Ren-Wang
- ORCID
- Venue
- Oncogene
- Published
- 2018-08-31
- Volume
- 38
- Issue
- 5
- Pages
- 622-636
- ISSN
- 0950-9232 (ISSN-L)
- 1476-5594
- OpenAlex
- W2889171823
- Cited by
- 55
- References
- 47
- Citations by year
- 2026: 3 · 2025: 6 · 2024: 6 · 2023: 7 · 2022: 8 · 2021: 12 · 2020: 6 · 2019: 6 · 2018: 1
- FWCI
- 2.31
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Oncogene (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- mTOR signaling, KRAS mutation, lung adenocarcinoma, chemoresistance, mTOR inhibitors, combination therapy, drug synergy, targeted therapy, oncogenic KRAS
- MeSH terms
- Adenocarcinoma of Lung, Animals, Humans, Lung Neoplasms, Proto-Oncogene Proteins p21(ras), Mice, Knockout, Drug Resistance, Neoplasm, Mice, TOR Serine-Threonine Kinases
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