Villa Matteo, Malighetti Federica, Sala Elisa, Sharma Geeta G, Arosio Giulia, Gemelli Maria, Manfroni Chiara, Fontana Diletta, Cordani Nicoletta, Meneveri Raffaella, Zambon Alfonso, Piazza Rocco, Pagni Fabio, Cortinovis Diego, Mologni Luca
Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy.
SC Medical Oncology, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy.
NPJ Precis Oncol. 2024 Mar 6;8(1):29. doi: 10.1038/s41698-024-00498-w.
ALK and ROS1 fusions are effectively targeted by tyrosine kinase inhibitors (TKIs), however patients inevitably relapse after an initial response, often due to kinase domain mutations. We investigated circulating DNA from TKI-relapsed NSCLC patients by deep-sequencing. New EML4::ALK substitutions, L1198R, C1237Y and L1196P, were identified in the plasma of NSCLC ALK patients and characterized in a Ba/F3 cell model. Variants C1237Y and L1196P demonstrated pan-inhibitor resistance across 5 clinical and 2 investigational TKIs.
间变性淋巴瘤激酶（ALK）和ROS1融合蛋白可被酪氨酸激酶抑制剂（TKIs）有效靶向作用，然而患者在初始缓解后不可避免地会复发，这通常是由于激酶结构域突变所致。我们通过深度测序研究了TKI复发的非小细胞肺癌（NSCLC）患者的循环DNA。在NSCLC-ALK患者的血浆中鉴定出了新的棘皮动物微管相关蛋白样4（EML4）::ALK替代突变，即L1198R、C1237Y和L1196P，并在Ba/F3细胞模型中对其进行了表征。C1237Y和L1196P变体对5种临床用和2种研究用TKI均表现出泛抑制剂耐药性。
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