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Genetic correlation of crizotinib efficacy and resistance in ALK- rearranged non-small-cell lung cancer.
- Source :
-
Lung Cancer (01695002) . Sep2022, Vol. 171, p18-25. 8p. - Publication Year :
- 2022
-
Abstract
- • Insight into the mutational landscape of ALK-positive advanced NSCLC. • EML4-ALK v3 and TP53 alterations correlate with unfavorable PFS on first-line crizotinib. • EML4-ALK v3 demonstrates a distinct resistance landscape from the non-v3 subset. • Bypass and downstream signaling pathway alterations as potential resistance mechanisms to first-line crizotinib. Crizotinib remains one of the most commonly used targeted therapies for ALK fusion-positive patients. However, the mutational profiles and mechanisms of resistance to first-line crizotinib treatment remain to be thoroughly examined. We retrospectively reviewed 125 ALK -positive patients with histological and/or cytological diagnosis of NSCLC. Of these, baseline samples were available from 62 patients and 63 had resistance samples following first-line crizotinib treatment, with 18 patients having paired baseline and resistance samples. All patients were genetically profiled by NGS using a 139 lung cancer gene panel (Pulmocan®, Nanjing Geneseeq Technology Inc.). Survival associations of progression-free survival (PFS) and resistance mechanisms were evaluated in relation to ALK fusion variants and background genetic alterations. The median age of the cohort was 53 years old (range 26–78; 46.4 % females). Three novel ALK fusion partners were identified, including PSME4, cullin3 (CUL3) and coiled-coil domain containing 85A (CCDC85A). Among the different ALK fusion genes, patients carrying the v3 variant experienced worse PFS outcome compared with other non-v3 fusions (P = 0.01) in response to first-line crizotinib. Profiling of the genetic landscape revealed TP53 as the most frequently co-mutated gene, alterations of which were associated with unfavorable outcome (P = 0.024) and were among the secondary acquired mutations in the resistance samples. Examinations of the resistance mechanisms showed that the v3 variant was more likely to acquire ALK activating mutations (P = 0.04). Off-target resistance mechanisms included mutations in genes in the RAS/MAPK and its parallel pathway genes, such as ERBB2 , BRAF , KRAS , FGFR3 , NF1 and CREBBP. In this study, through profiling of the mutational landscape of ALK-positive advanced NSCLCs both at baseline and disease progression, we characterized resistance mechanisms and molecular correlations of PFS in response to first-line crizotinib. Our findings may facilitate rational selection of subsequent ALK TKIs in the clinic. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 01695002
- Volume :
- 171
- Database :
- Academic Search Index
- Journal :
- Lung Cancer (01695002)
- Publication Type :
- Academic Journal
- Accession number :
- 158513630
- Full Text :
- https://doi.org/10.1016/j.lungcan.2022.07.011