International journal of clinical pharmacology and therapeutics · 2025
Rare systemic skin hyperpigmentation associated with osimertinib: A case report.
Клинический случайСтатьяНазвание и аннотация: Перевод пока не подготовлен
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Tu Xinyi, Zeng Xiangyu, Sun Yaoliang, Ouyang Yaobin, Zhu Lingling, Yin Ping, Pavelko Kevin, Leon-Ferre Roberto, Jiang Yanxia, Dong Haidong, Carter Jodi, Zhu Shouhai, Sarkaria Jann N, Wang Liewei, Huang Jinzhou, Luo Kuntian, Han Yiqun, Wu Zheming, Lou Zhenkun, Mutter Robert W
Аннотация
Our research uncovers a role for ATR in responding to ECM stiffness and promoting epithelial-to-mesenchymal transition (EMT) and metastasis. ATR, when deubiquitinated and upregulated by USP21 under enhanced ECM stiffness conditions, phosphorylates the nuclear protein SUN2, which promotes β-catenin nuclear translocation and EMT. ATM-mediated EMT promotes polymorphonuclear myeloid-derived suppressor cell recruitment and inhibits CD103+ dendritic cells, fostering an immunosuppressive tumor milieu. ATR inhibition disrupts this malignant cascade by promoting mesenchymal-to-epithelial transition to enhance antitumor immunity and mitigate metastases. Consistently, circulating HLA-DR+ dendritic cells were also enhanced following treatment with the ATR inhibitor berzosertib in patients with therapeutically resistant early-stage breast cancer. Our data suggest that ATR-targeted therapy may be optimized by considering both DNA damage-dependent and EMT-inducing effects of ATR.