mTOR mediates a mechanism of resistance to chemotherapy and defines a rational combination strategy to treat KRAS-mutant lung cancer.
Détails
ID Serval
serval:BIB_6647FA663BB8
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
mTOR mediates a mechanism of resistance to chemotherapy and defines a rational combination strategy to treat KRAS-mutant lung cancer.
Périodique
Oncogene
ISSN
1476-5594 (Electronic)
ISSN-L
0950-9232
Statut éditorial
Publié
Date de publication
01/2019
Peer-reviewed
Oui
Volume
38
Numéro
5
Pages
622-636
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Publication Status: ppublish
Résumé
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.
Mots-clé
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
Création de la notice
29/06/2020 9:31
Dernière modification de la notice
30/06/2020 5:26