Titre
mTOR mediates a mechanism of resistance to chemotherapy and defines a rational combination strategy to treat KRAS-mutant lung cancer.
Type
article
Institution
Externe
Périodique
Auteur(s)
Liang, S.Q.
Auteure/Auteur
Bührer, E.D.
Auteure/Auteur
Berezowska, S.
Auteure/Auteur
Marti, T.M.
Auteure/Auteur
Xu, D.
Auteure/Auteur
Froment, L.
Auteure/Auteur
Yang, H.
Auteure/Auteur
Hall, SRR
Auteure/Auteur
Vassella, E.
Auteure/Auteur
Yang, Z.
Auteure/Auteur
Kocher, G.J.
Auteure/Auteur
Amrein, M.A.
Auteure/Auteur
Riether, C.
Auteure/Auteur
Ochsenbein, A.F.
Auteure/Auteur
Schmid, R.A.
Auteure/Auteur
Peng, R.W.
Auteure/Auteur
Liens vers les personnes
ISSN
1476-5594
Statut éditorial
Publié
Date de publication
2019-01
Volume
38
Numéro
5
Première page
622
Dernière page/numéro d’article
636
Peer-reviewed
Oui
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.
Sujets
PID Serval
serval:BIB_6647FA663BB8
PMID
Date de création
2020-06-29T08:31:23.484Z
Date de création dans IRIS
2025-05-20T21:21:54Z