[HTML][HTML] Targeting ER stress–induced autophagy overcomes BRAF inhibitor resistance in melanoma

XH Ma, SF Piao, S Dey, Q Mcafee… - The Journal of …, 2014 - Am Soc Clin Investig
XH Ma, SF Piao, S Dey, Q Mcafee, G Karakousis, J Villanueva, LS Hart, S Levi, J Hu…
The Journal of clinical investigation, 2014Am Soc Clin Investig
Melanomas that result from mutations in the gene encoding BRAF often become resistant to
BRAF inhibition (BRAFi), with multiple mechanisms contributing to resistance. While therapy-
induced autophagy promotes resistance to a number of therapies, especially those that
target PI3K/mTOR signaling, its role as an adaptive resistance mechanism to BRAFi is not
well characterized. Using tumor biopsies from BRAFV600E melanoma patients treated
either with BRAFi or with combined BRAF and MEK inhibition, we found that BRAFi-resistant …
Melanomas that result from mutations in the gene encoding BRAF often become resistant to BRAF inhibition (BRAFi), with multiple mechanisms contributing to resistance. While therapy-induced autophagy promotes resistance to a number of therapies, especially those that target PI3K/mTOR signaling, its role as an adaptive resistance mechanism to BRAFi is not well characterized. Using tumor biopsies from BRAFV600E melanoma patients treated either with BRAFi or with combined BRAF and MEK inhibition, we found that BRAFi-resistant tumors had increased levels of autophagy compared with baseline. Patients with higher levels of therapy-induced autophagy had drastically lower response rates to BRAFi and a shorter duration of progression-free survival. In BRAFV600E melanoma cell lines, BRAFi or BRAF/MEK inhibition induced cytoprotective autophagy, and autophagy inhibition enhanced BRAFi-induced cell death. Shortly after BRAF inhibitor treatment in melanoma cell lines, mutant BRAF bound the ER stress gatekeeper GRP78, which rapidly expanded the ER. Disassociation of GRP78 from the PKR-like ER-kinase (PERK) promoted a PERK-dependent ER stress response that subsequently activated cytoprotective autophagy. Combined BRAF and autophagy inhibition promoted tumor regression in BRAFi-resistant xenografts. These data identify a molecular pathway for drug resistance connecting BRAFi, the ER stress response, and autophagy and provide a rationale for combination approaches targeting this resistance pathway.
The Journal of Clinical Investigation