Abstract
ER stress-induced autophagy confers resistance to BRAF inhibitors in BRAF-mutant melanoma.
Major finding: ER stress-induced autophagy confers resistance to BRAF inhibitors in BRAF-mutant melanoma.
Concept: BRAF inhibitors stimulate PERK-dependent ER stress by inducing binding of BRAFV600E to GRP78.
Impact: Autophagy inhibitors may enhance the efficacy of BRAF inhibition in patients with BRAF-mutant melanoma.
Targeted inhibition of BRAF or its downstream effector MEK is effective in a large percentage of melanoma patients harboring activating BRAFV600 mutations, but resistance rapidly develops. Autophagy has emerged as a common prosurvival mechanism against a number of targeted anticancer therapies, although its role in BRAF inhibitor resistance is not fully understood. By examining paired tumor biopsies from patients with BRAFV600-driven melanoma treated with either a BRAF inhibitor or a combination of BRAF and MEK inhibitors, Ma and colleagues found that levels of autophagy were increased compared with pretreatment levels in 74% of samples. Increased autophagy following treatment was correlated with a markedly decreased response rate to BRAF inhibition as well as reduced progression-free survival. Inhibition or knockdown of BRAF also induced autophagy in BRAFV600E–expressing melanoma cell lines independent of their sensitivity to BRAF inhibition, but autophagy inhibition most significantly enhanced BRAF inhibitor–induced growth suppression in BRAF inhibitor–resistant cell lines, suggesting that BRAF inhibitor–induced autophagy is cytoprotective and that BRAF inhibitor–resistant cells may be more reliant on autophagy for survival. Mechanistically, BRAF inhibition upregulated multiple markers of the ER stress response and triggered the association of BRAFV600E with the ER chaperone GRP78, which correlated with a dissociation of GRP78 from the known ER stress response activator PKR-like ER-kinase (PERK). BRAF inhibition stimulated PERK activation and knockdown or inhibition of PERK reduced BRAF inhibitor-induced autophagy and enhanced apoptosis, indicating that PERK-dependent ER stress activates cytoprotective autophagy in response to BRAF inhibition. Important, in concordance with these findings, combined inhibition of BRAFV600E and autophagy induced significant regression of BRAF inhibitor-resistant xenografts in nude mice. Although further characterization of the functional role of BRAFV600E in ER stress-induced autophagy is needed, these results provide a rationale for clinical evaluation of concomitant use of BRAF and autophagy inhibitors in patients with advanced BRAF-mutant melanoma.
