A Novel Sequentially Evolved EML4-ALK Variant 3 G1202R/S1206Y Double Mutation In Cis Confers Resistance to Lorlatinib: A Brief Report and Literature Review

• Published in: JTO clinical and research reports Vol. 2; no. 1; p. 100116
• Main Authors: Zhu, Viola W., Nagasaka, Misako, Madison, Russell, Schrock, Alexa B., Cui, Jean, Ou, Sai-Hong Ignatius
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 01.01.2021; Elsevier
• Subjects: ALK+ NSCLC; Brief Report; Double mutation; G1202R; Lorlatinib resistance; S1206Y; Double mutation; G1202R; S1206Y; Lorlatinib resistance; ALK+ NSCLC
• ISSN: 2666-3643; 2666-3643
• DOI: 10.1016/j.jtocrr.2020.100116

Lorlatinib is a third-generation ALK inhibitor that can overcome the largest number of acquired ALK resistance mutations, including the solvent-front mutation G1202R. Here, we report, for the first time, a novel, sequentially-evolved EML4-ALK variant 3 G1202R/S1206Y double mutation in cis detected in a patient with ALK-positive NSCLC after disease progression on sequential crizotinib, alectinib, and then lorlatinib. Three-dimensional computer modeling of this double mutation and other G1202R-based double mutations with lorlatinib (ALK G1202R/L1196M, ALK G1202R/F1174C, ALK G1202R/l1198F, ALK G1202R/G1269A) were provided to reveal how these double mutations may confer resistance to lorlatinib through diverse steric hindrances in the ALK kinase domain. In addition, we performed a comprehensive literature review on published acquired double or triple ALK mutations that are resistant to lorlatinib from both patient samples and in vitro mutagenesis experiments.