Targeting Discoidin Domain Receptors DDR1 and DDR2 overcomes matrix-mediated tumor cell adaptation and tolerance to BRAF-targeted therapy in melanoma

Resistance to BRAF/MEK inhibitor therapy in BRAF(V600)-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 BRAF(V600) pathway inhibition in melanoma. We demonstrate that physical and structural cues from fibroblast-derived ECM abrogate antiproliferative 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/IKK alpha/NF-kappa B2 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.

Automated summary

The study reveals that physical and structural signals from fibroblast-derived ECM can cause the antiproliferative responses to BRAF/MEK inhibitors to fail in melanoma. Drug-induced linear clustering of DDR1 and DDR2 mediates ECM-mediated drug resistance. Targeting DDR1 and DDR2 can overcome resistance to BRAF-targeted therapy mediated by ECM.