Drug resistance of ALK mutants

Aberrant ALK activity arises through fusions, point mutations, overexpression or amplifications and has been shown to be an oncogenic driver in a number of cancers including anaplastic large cell lymphoma (ALCL), non-small cell lung cancer (NSCLC), inflammatory myofibroblastic tumors (IMTs) neuroblastomas and more (reviewed in Della Corte et al, 2018; Lin et al, 2017). As a result, ALK is a promising therapeutic target for inhibition with tyrosine kinase inhibitors. Crizotinib, ceritinib, brigatinib, alectinib and lorlatinib are all approved for the treatment of ALK-driven cancers, however resistance commonly develops either as a result of accumulating secondary mutations, or through activation of bypass pathways that remove the dependence on ALK signaling (reviewed in Della Corte et al, 2017; Roskoski, 2013; Lin et al, 2017).

异常的ALK活性可通过融合、点突变、过表达或扩增产生，并在包括间变性大细胞淋巴瘤（ALCL）、非小细胞肺癌（NSCLC）、炎症性肌成纤维细胞瘤（IMTs）、神经母细胞瘤等多种癌症中表现出致癌驱动作用（如Della Corte等，2018年；Lin等，2017年所述）。因此，ALK成为抑制性酪氨酸激酶抑制剂治疗的一个极具潜力的靶点。克唑替尼、塞瑞替尼、布加替尼、阿来替尼和洛拉替尼等药物均获得批准用于治疗ALK驱动型癌症，然而，耐药性通常由于累积的继发性突变或通过激活旁路途径以消除对ALK信号依赖而发展（如Della Corte等，2017年；Roskoski，2013年；Lin等，2017年所述）。