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

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

Abstract 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 underly...

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Main Authors: Ilona Berestjuk, Margaux Lecacheur, Alexandrine Carminati, Serena Diazzi, Christopher Rovera, Virginie Prod’homme, Mickael Ohanna, Ana Popovic, Aude Mallavialle, Frédéric Larbret, Sabrina Pisano, Stéphane Audebert, Thierry Passeron, Cédric Gaggioli, Christophe A Girard, Marcel Deckert, Sophie Tartare‐Deckert
Format: Article
Language:English
Published: Springer Nature 2021-12-01
Series:EMBO Molecular Medicine
Subjects:
DDR
extracellular matrix
melanoma
NF‐κB2
therapeutic resistance
Online Access:https://doi.org/10.15252/emmm.201911814
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Summary:Abstract 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.
ISSN:1757-4676
1757-4684

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