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

• Published in: EMBO molecular medicine Vol. 14; no. 2; pp. e11814 - n/a
• Main Authors: Berestjuk, Ilona, Lecacheur, Margaux, Carminati, Alexandrine, Diazzi, Serena, Rovera, Christopher, Prod’homme, Virginie, Ohanna, Mickael, Popovic, Ana, Mallavialle, Aude, Larbret, Frédéric, Pisano, Sabrina, Audebert, Stéphane, Passeron, Thierry, Gaggioli, Cédric, Girard, Christophe A, Deckert, Marcel, Tartare‐Deckert, Sophie
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 07.02.2022; EMBO Press; Wiley Open Access; John Wiley and Sons Inc; Springer Nature
• Subjects: Adaptation; Biopsy; Cancer therapies; Collagen; DDR; Discoidin Domain Receptor 1; Discoidin Domain Receptor 2; Drug resistance; EMBO03; EMBO38; Extracellular matrix; Fibroblasts; Glycoproteins; Humans; Imatinib; Immunological tolerance; Kinases; Life Sciences; MEK inhibitors; Melanoma; Melanoma - pathology; Microenvironments; Mutation; Neoplasm Recurrence, Local; NF‐κB2; Patients; Protein-tyrosine kinase; Proto-Oncogene Proteins B-raf; Receptors, Mitogen - chemistry; therapeutic resistance; Tumor Microenvironment; Tumors; Xenografts; melanoma; DDR; therapeutic resistance; extracellular matrix; NF‐κB2; NF-κB2
• ISSN: 1757-4676; 1757-4684
• DOI: 10.15252/emmm.201911814

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 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. Synopsis 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. Adhesion of BRAF‐mutated melanoma cells to extracellular matrix generated from melanoma associated fibroblasts (MAF) confers tolerance to BRAF and MEK inhibition. Collagen receptors DDR promote tumor cell survival and matrix‐mediated drug resistance (MMDR) to combined MAPK targeted agents through NIK and non‐canonical NFκB2 signaling. DDR inhibition increases response to oncogenic BRAF inhibition, suppresses therapy‐induced collagen remodeling and induces tumor cell death in melanoma xenografts. Triple‐drug combination using BRAF/MEK inhibitors and DDR inhibitor such as imatinib, a clinically approved drug for leukemia, is proposed as a novel therapeutic strategy against disease relapse. Graphical Abstract 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.