MET Exon 14 Skipping and Novel Actionable Variants: Diagnostic and Therapeutic Implications in Latin American Non-Small-Cell Lung Cancer Patients

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dc.contributor.authorRivas, Solange
dc.contributor.authorSepúlveda, Romina V.
dc.contributor.authorTapia, Ignacio
dc.contributor.authorEstay, Catalina
dc.contributor.authorSoto, Vicente
dc.contributor.authorBlanco, Alejandro
dc.contributor.authorGonzález, Evelin
dc.contributor.authorArmisen, Ricardo
dc.date.accessioned2025-06-10T18:20:05Z
dc.date.available2025-06-10T18:20:05Z
dc.date.issued2024-12
dc.descriptionIndexación: Scopus.
dc.description.abstractTargeted therapy indications for actionable variants in non-small-cell lung cancer (NSCLC) have primarily been studied in Caucasian populations, with limited data on Latin American patients. This study utilized a 52-genes next-generation sequencing (NGS) panel to analyze 1560 tumor biopsies from NSCLC patients in Chile, Brazil, and Peru. The RNA sequencing reads and DNA coverage were correlated to improve the detection of the actionable MET exon 14 skipping variant (METex14). The pathogenicity of MET variants of uncertain significance (VUSs) was assessed using bioinformatic methods, based on their predicted driver potential. The effects of the predicted drivers VUS T992I and H1094Y on c-MET signaling activation, proliferation, and migration were evaluated in HEK293T, BEAS-2B, and H1993 cell lines. Subsequently, c-Met inhibitors were tested in 2D and 3D cell cultures, and drug affinity was determined using 3D structure simulations. The prevalence of MET variants in the South American cohort was 8%, and RNA-based diagnosis detected 27% more cases of METex14 than DNA-based methods. Notably, 20% of METex14 cases with RNA reads below the detection threshold were confirmed using DNA analysis. The novel actionable T992I and H1094Y variants induced proliferation and migration through c-Met/Akt signaling. Both variants showed sensitivity to crizotinib and savolitinib, but the H1094Y variant exhibited reduced sensitivity to capmatinib. These findings highlight the importance of RNA-based METex14 diagnosis and reveal the drug sensitivity profiles of novel actionable MET variants from an understudied patient population. © 2024 by the authors.
dc.description.accesoabiertoSI
dc.description.urihttps://www-scopus-com.recursosbiblioteca.unab.cl/record/display.uri?eid=2-s2.0-85213248074&origin=resultslist&sort=plf-f&src=s&sid=c7a0edc692466c5b2dfd41dba6b8f91e&sot=aff&sdt=cl&cluster=scofreetoread%2C%22all%22%2Ct%2Bscosubtype%2C%22ar%22%2Ct&s=AF-ID%2860002636%29+AND+SUBJAREA%28CHEM%29&sl=34&sessionSearchId=c7a0edc692466c5b2dfd41dba6b8f91e&relpos=7
dc.identifier.citationInternational Journal of Molecular Sciences Open Access Volume 25, Issue 24 December 2024 Article number 13715
dc.identifier.doi10.3390/ijms252413715
dc.identifier.generoM
dc.identifier.issn16616596
dc.identifier.urihttps://repositorio.unab.cl/handle/ria/65169
dc.language.isoen
dc.publisherMultidisciplinary Digital Publishing Institute (MDPI)
dc.rights.licenseAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectc-Met inhibitors
dc.subjectMET exon 14 skipping
dc.subjectNext-generation sequencing
dc.subjectNon-small-cell lung cancer
dc.titleMET Exon 14 Skipping and Novel Actionable Variants: Diagnostic and Therapeutic Implications in Latin American Non-Small-Cell Lung Cancer Patients
dc.typeArtículo
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