title: Targeting ER stress-induced autophagy overcomes BRAF inhibitor resistance in melanoma.
abstract: 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 BRAF(V600E) 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 BRAF(V600E) 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.
authors.forename: Xiao-Hong
authors.initials: XH
authors.lastname: Ma
authors.forename: Sheng-Fu
authors.initials: SF
authors.lastname: Piao
authors.forename: Souvik
authors.initials: S
authors.lastname: Dey
authors.forename: Quentin
authors.initials: Q
authors.lastname: McAfee
authors.forename: Giorgos
authors.initials: G
authors.lastname: Karakousis
authors.forename: Jessie
authors.initials: J
authors.lastname: Villanueva
authors.forename: Lori S
authors.initials: LS
authors.lastname: Hart
authors.forename: Samuel
authors.initials: S
authors.lastname: Levi
authors.forename: Janice
authors.initials: J
authors.lastname: Hu
authors.forename: Gao
authors.initials: G
authors.lastname: Zhang
authors.forename: Rossitza
authors.initials: R
authors.lastname: Lazova
authors.forename: Vincent
authors.initials: V
authors.lastname: Klump
authors.forename: John M
authors.initials: JM
authors.lastname: Pawelek
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Xu
authors.forename: Wei
authors.initials: W
authors.lastname: Xu
authors.forename: Lynn M
authors.initials: LM
authors.lastname: Schuchter
authors.forename: Michael A
authors.initials: MA
authors.lastname: Davies
authors.forename: Meenhard
authors.initials: M
authors.lastname: Herlyn
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Winkler
authors.forename: Constantinos
authors.initials: C
authors.lastname: Koumenis
authors.forename: Ravi K
authors.initials: RK
authors.lastname: Amaravadi
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D020935:MAP Kinase Signaling System; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D020125:Mutation, Missense; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology*; D000077484:Vemurafenib; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; C000717248:Hspa5 protein, mouse; D007211:Indoles; C528407:PLX 4720; D013449:Sulfonamides; D000077484:Vemurafenib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf