A Novel Sequentially Evolved EML4-ALK Variant 3 G1202R/S1206Y Double Mutation In Cis Confers Resistance to Lorlatinib: A Brief Report and Literature Review
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 i...
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Published in | JTO clinical and research reports Vol. 2; no. 1; p. 100116 |
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Main Authors | , , , , , |
Format | Journal Article |
Language | English |
Published |
Elsevier Inc
01.01.2021
Elsevier |
Subjects | |
Online Access | Get full text |
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Summary: | 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. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 2666-3643 2666-3643 |
DOI: | 10.1016/j.jtocrr.2020.100116 |