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

Oncogene
Shun-Qing LiangRen-Wang Peng

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...Continue Reading

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Citations

Sep 3, 2019·Current Topics in Medicinal Chemistry·Hao HeLei Zheng
Oct 16, 2019·Frontiers in Oncology·Haitang YangRen-Wang Peng
Jun 21, 2020·International Journal of Molecular Sciences·Iris Z UrasEmilio Casanova
Sep 6, 2019·Current Topics in Medicinal Chemistry·Hai-Zhou WuYan Cheng
Apr 21, 2021·Journal of Experimental & Clinical Cancer Research : CR·Yanyun GaoThomas Michael Marti
Aug 4, 2021·Nature Reviews. Cancer·Lucilla FabbriStéphan Vagner

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Methods Mentioned

BETA
transfection
xenograft
surgical resections
PCR
Flow
Assay
Infrared Imaging

Software Mentioned

Adobe Photoshop CS6
ELDA
7500
CompuSyn
GraphPad Prism

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