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

Details

Serval ID
serval:BIB_6647FA663BB8
Type
Article: article from journal or magazin.
Collection
Publications
Title
mTOR mediates a mechanism of resistance to chemotherapy and defines a rational combination strategy to treat KRAS-mutant lung cancer.
Journal
Oncogene
Author(s)
Liang S.Q., Bührer E.D., Berezowska S., Marti T.M., Xu D., Froment L., Yang H., Hall SRR, Vassella E., Yang Z., Kocher G.J., Amrein M.A., Riether C., Ochsenbein A.F., Schmid R.A., Peng R.W.
ISSN
1476-5594 (Electronic)
ISSN-L
0950-9232
Publication state
Published
Issued date
01/2019
Peer-reviewed
Oui
Volume
38
Number
5
Pages
622-636
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
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.
Keywords
Adenocarcinoma of Lung/drug therapy, Adenocarcinoma of Lung/enzymology, Adenocarcinoma of Lung/genetics, Adenocarcinoma of Lung/pathology, Animals, Drug Resistance, Neoplasm, Humans, Lung Neoplasms/drug therapy, Lung Neoplasms/enzymology, Lung Neoplasms/genetics, Lung Neoplasms/pathology, Mice, Mice, Knockout, Proto-Oncogene Proteins p21(ras)/genetics, Proto-Oncogene Proteins p21(ras)/metabolism, TOR Serine-Threonine Kinases/genetics, TOR Serine-Threonine Kinases/metabolism
Pubmed
Web of science
Create date
29/06/2020 9:31
Last modification date
30/06/2020 5:26
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