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.
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DOI：
10.15252/emmm.201911814
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发表时间：
2022-02-07
影响因子：
11.1
通讯作者：
Tartare-Deckert S
中科院分区：
文献类型：
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作者：
Berestjuk I;Lecacheur M;Carminati A;Diazzi S;Rovera C;Prod'homme V;Ohanna M;Popovic A;Mallavialle A;Larbret F;Pisano S;Audebert S;Passeron T;Gaggioli C;Girard CA;Deckert M;Tartare-Deckert S
BRAFV 600突变的晚期黑色素瘤对BRAF/MEK抑制剂治疗的耐药性仍然是限制患者获益的主要障碍。包括细胞外基质（ECM）在内的微环境成分可以支持肿瘤细胞对靶向治疗的适应和耐受;然而，其潜在机制仍然知之甚少。在这里，我们研究了黑色素瘤中基质介导的耐药（MMDR）对BRAFV 600通路抑制的反应过程。我们证明，来自成纤维细胞来源的ECM的物理和结构线索消除了对BRAF/MEK抑制的抗增殖反应。MMDR由药物诱导的磷酸化DDR 1和DDR2（两种酪氨酸激酶胶原蛋白受体）的线性聚集介导。DDR 1和DDR2的消耗和药理学靶向克服了ECM介导的对BRAF靶向治疗的抗性。在异种移植物中，伊马替尼靶向DDR增强了BRAF抑制剂的疗效，抵消了药物诱导的胶原蛋白重塑，并延迟了肿瘤复发。从机制上讲，DDR依赖性MMDR促进了靶向的促生存NIK/IKKα/NF-κB2通路。这些发现揭示了富含胶原蛋白的基质和DDR在肿瘤细胞适应和抵抗中的新作用。它们还提供了对环境介导的耐药性的重要见解，以及靶向DDR信号传导与黑色素瘤靶向治疗相结合的临床前原理。对MAPK靶向治疗的耐药性仍然是黑色素瘤治疗的主要挑战。这项研究表明，BRAF/MEK抑制剂组合诱导胶原蛋白重塑，促进盘状结构域受体（DDR）的激活，并开启耐药途径。以复员方案为目标克服了这一途径。
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.