| Added by | tchardes |
|---|---|
| Group name | EquipeELC |
| Item Type | Journal Article |
| Title | Targeting Discoidin Domain Receptors DDR1 and DDR2 overcomes matrix-mediated tumor cell adaptation and tolerance to BRAF-targeted therapy in melanoma |
| Creator | Berestjuk et al. |
| Author | Ilona Berestjuk |
| Author | Margaux Lecacheur |
| Author | Alexandrine Carminati |
| Author | Serena Diazzi |
| Author | Christopher Rovera |
| Author | Ana Popovic |
| Author | Aude Mallavialle |
| Author | Frédéric Larbret |
| Author | Sabrina Pisano |
| Author | Stéphane Audebert |
| Author | Thierry Passeron |
| Author | Cédric Gaggioli |
| Author | Christophe A. Girard |
| Author | Marcel Deckert |
| Author | Sophie Tartare-Deckert |
| 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/IKK?/NF-?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. |
| Publication | EMBO molecular medicine |
| Pages | e11814 |
| Date | 2021-12-27 |
| Journal Abbr | EMBO Mol Med |
| Language | eng |
| DOI | 10.15252/emmm.201911814 |
| ISSN | 1757-4684 |
| Library Catalog | PubMed |
| Extra | PMID: 34957688 |
| Tags | DDR, extracellular matrix, NF-?B2, original |
| Date Added | 2022/01/14 - 09:42:39 |
| Date Modified | 2022/02/09 - 16:02:36 |
| Notes and Attachments | PubMed entry (Attachment) Texte intégral (Attachment) |
Institut de Recherche en Cancérologie de
