Resistance to BRAF/MEK inhibitor therapy in BRAFV600‐mutated advanced melanoma remains a major obstacle that limits patient benefit.,Microenvironment components including the extracellular matrix (ECM) can support tumor cell adaptation and tolerance to targeted therapy; however, the underlying mechanisms remain poorly understood.,Here, we investigated the process of matrix‐mediated drug resistance (MMDR) in response to BRAFV600 pathway inhibition in melanoma.,We demonstrate that physical and structural cues from fibroblast‐derived ECM abrogate anti‐proliferative responses to BRAF/MEK inhibition.,MMDR is mediated by drug‐induced linear clustering of phosphorylated DDR1 and DDR2, two tyrosine kinase collagen receptors.,Depletion and pharmacological targeting of DDR1 and DDR2 overcome ECM‐mediated resistance to BRAF‐targeted therapy.,In xenografts, targeting DDR with imatinib enhances BRAF inhibitor efficacy, counteracts drug‐induced collagen remodeling, and delays tumor relapse.,Mechanistically, DDR‐dependent MMDR fosters a targetable pro‐survival NIK/IKKα/NF‐κB2 pathway.,These findings reveal a novel role for a collagen‐rich matrix and DDR in tumor cell adaptation and resistance.,They also provide important insights into environment‐mediated drug resistance and a preclinical rationale for targeting DDR signaling in combination with targeted therapy in melanoma.,Resistance to MAPK targeted therapy remains a major challenge in melanoma management.,This study shows that BRAF/MEK inhibitor combination induces collagen remodeling that fosters activation of Discoidin Domain Receptors (DDR) and turns on a drug tolerant pathway.,Targeting DDR overcomes this pathway.
Uveal melanoma is a clinically distinct and particularly lethal subtype of melanoma originating from melanocytes in the eye.,Here, we performed multi-region DNA sequencing of primary uveal melanomas and their matched metastases from 35 patients.,We observed novel driver mutations and established the order in which these and known driver mutations undergo selection.,Metastases had genomic alterations distinct from their primary tumors, and metastatic dissemination sometimes occurred early during the development of the primary tumor.,Our study offers new insights into the genetics and evolution of this melanoma subtype, providing potential biomarkers for progression and therapy.