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Review

Autophagy Inhibition in BRAF-Driven Cancers

by 1 and 1,2,*
1
Huntsman Cancer Institute, Salt Lake City, UT 84112, USA
2
Department of Dermatology, University of Utah, Salt Lake City, UT 84112, USA
*
Author to whom correspondence should be addressed.
Academic Editor: Zhixiang Wang
Cancers 2021, 13(14), 3498; https://doi.org/10.3390/cancers13143498
Received: 21 June 2021 / Revised: 10 July 2021 / Accepted: 11 July 2021 / Published: 13 July 2021
(This article belongs to the Collection Drug Resistance and Novel Therapies in Cancers)
BRAF is a protein kinase that is frequently mutationally activated in cancer. Mutant BRAF can be pharmacologically inhibited, which in combination with blockade of its direct effector, MEK1/2, is an FDA-approved therapeutic strategy for several BRAF-mutated cancer patients, such as melanoma, non-small-cell lung carcinoma, and thyroid cancer. However, therapy resistance is a major clinical challenge, highlighting the need for comprehensive investigations on the biological causes of such resistance, as well as to develop novel therapeutic strategies to improve patient survival. Autophagy is a cellular recycling process, which has been shown to allow cancer cells to escape from BRAF inhibition. Combined blockade of autophagy and BRAF signaling is a novel therapeutic strategy that is currently being tested in clinical trials. This review describes the relationship between BRAF-targeted therapy and autophagy regulation and discusses possible future treatment strategies.
Several BRAF-driven cancers, including advanced BRAFV600E/K-driven melanoma, non-small-cell lung carcinoma, and thyroid cancer, are currently treated using first-line inhibitor combinations of BRAFV600E plus MEK1/2. However, despite the success of this vertical inhibition strategy, the durability of patient response is often limited by the phenomenon of primary or acquired drug resistance. It has recently been shown that autophagy, a conserved cellular recycling process, is increased in BRAF-driven melanoma upon inhibition of BRAFV600E signaling. Autophagy is believed to promote tumor progression of established tumors and also to protect cancer cells from the cytotoxic effects of chemotherapy. To this end, BRAF inhibitor (BRAFi)-resistant cells often display increased autophagy compared to responsive lines. Several mechanisms have been proposed for BRAFi-induced autophagy, such as activation of the endoplasmic reticulum (ER) stress gatekeeper GRP78, AMP-activated protein kinase, and transcriptional regulation of the autophagy regulating transcription factors TFEB and TFE3 via ERK1/2 or mTOR inhibition. This review describes the relationship between BRAF-targeted therapy and autophagy regulation, and discusses possible future treatment strategies of combined inhibition of oncogenic signaling plus autophagy for BRAF-driven cancers. View Full-Text
Keywords: BRAF; MEK1/2; autophagy; targeted therapy; drug resistance; metabolism BRAF; MEK1/2; autophagy; targeted therapy; drug resistance; metabolism
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MDPI and ACS Style

Foth, M.; McMahon, M. Autophagy Inhibition in BRAF-Driven Cancers. Cancers 2021, 13, 3498. https://doi.org/10.3390/cancers13143498

AMA Style

Foth M, McMahon M. Autophagy Inhibition in BRAF-Driven Cancers. Cancers. 2021; 13(14):3498. https://doi.org/10.3390/cancers13143498

Chicago/Turabian Style

Foth, Mona, and Martin McMahon. 2021. "Autophagy Inhibition in BRAF-Driven Cancers" Cancers 13, no. 14: 3498. https://doi.org/10.3390/cancers13143498

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