Anaplastic lymphoma receptor tyrosine kinase C1156Y mutant (ALK C1156Y)

The Anaplastic lymphoma receptor tyrosine kinase (ALK) C1156Y mutant is a specific variant of the ALK protein, primarily identified as a mechanism of acquired resistance in patients with ALK-rearranged non-small cell lung cancer (NSCLC) [4, 8]. ALK is a member of the insulin receptor superfamily and plays a critical role in the development and function of the nervous system by regulating cell proliferation, survival, and differentiation [13, 21]. In oncogenic contexts, such as the EML4-ALK fusion, the kinase becomes constitutively active, driving malignant transformation through the activation of downstream signaling cascades like PI3K/AKT, MAPK/ERK, and STAT3 [13, 17]. The C1156Y mutation, located in the kinase domain, confers resistance to the first-generation inhibitor crizotinib and the second-generation inhibitor ceritinib by inducing allosteric effects that alter the active pocket's geometry [6, 16]. Despite this resistance, the C1156Y mutant remains sensitive to third-generation inhibitors such as lorlatinib and some second-generation agents like alectinib [4, 8, 21]. Notably, the C1156Y mutation can further evolve under selective pressure into compound mutations, such as C1156Y/L1198F, which paradoxically resensitizes the tumor to crizotinib while conferring high-level resistance to lorlatinib [1, 14].

Other names

CD246ALK tyrosine kinase receptor C1156YEML4-ALK C1156YAnaplastic lymphoma kinase C1156Yp80

Tyrosine kinase inhibition