Alterations in the pi3k pathway drive ...
Type de document :
Article dans une revue scientifique: Article de synthèse/Review paper
PMID :
URL permanente :
Titre :
Alterations in the pi3k pathway drive resistance to met inhibitors in nsclc harboring met exon 14 skipping mutations
Auteur(s) :
Jamme, Philippe [Auteur]
Miniaturisation pour la Synthèse, l’Analyse et la Protéomique - UAR 3290 [MSAP]
Miniaturisation pour la Synthèse, l'Analyse et la Protéomique (MSAP) - USR 3290
Fernandes, Marie [Auteur]
Copin, Marie-Christine [Auteur]
Descarpentries, Clotilde [Auteur]
Escande, Fabienne [Auteur]
Morabito, Angela [Auteur]
Miniaturisation pour la Synthèse, l’Analyse et la Protéomique - UAR 3290 [MSAP]
Cancer Heterogeneity, Plasticity and Resistance to Therapies (CANTHER) - UMR 9020 - UMR 1277
Gregoire, Valerie [Auteur]
Jamme, Matthieu [Auteur]
Baldacci, Simon [Auteur]
Centre Hospitalier Régional Universitaire [CHU Lille] [CHRU Lille]
Tulasne, David [Auteur]
Miniaturisation pour la Synthèse, l’Analyse et la Protéomique - UAR 3290 [MSAP]
Cancer Heterogeneity, Plasticity and Resistance to Therapies (CANTHER) - UMR 9020 - UMR 1277
Kherrouche, Zoulika [Auteur]
Miniaturisation pour la Synthèse, l’Analyse et la Protéomique - UAR 3290 [MSAP]
Cancer Heterogeneity, Plasticity and Resistance to Therapies (CANTHER) - UMR 9020 - UMR 1277
Cortot, Alexis B. [Auteur]
Miniaturisation pour la Synthèse, l’Analyse et la Protéomique - UAR 3290 [MSAP]
Miniaturisation pour la Synthèse, l'Analyse et la Protéomique (MSAP) - USR 3290
Fernandes, Marie [Auteur]
Copin, Marie-Christine [Auteur]
Descarpentries, Clotilde [Auteur]
Escande, Fabienne [Auteur]
Morabito, Angela [Auteur]
Miniaturisation pour la Synthèse, l’Analyse et la Protéomique - UAR 3290 [MSAP]
Cancer Heterogeneity, Plasticity and Resistance to Therapies (CANTHER) - UMR 9020 - UMR 1277
Gregoire, Valerie [Auteur]
Jamme, Matthieu [Auteur]
Baldacci, Simon [Auteur]
Centre Hospitalier Régional Universitaire [CHU Lille] [CHRU Lille]
Tulasne, David [Auteur]
Miniaturisation pour la Synthèse, l’Analyse et la Protéomique - UAR 3290 [MSAP]
Cancer Heterogeneity, Plasticity and Resistance to Therapies (CANTHER) - UMR 9020 - UMR 1277
Kherrouche, Zoulika [Auteur]
Miniaturisation pour la Synthèse, l’Analyse et la Protéomique - UAR 3290 [MSAP]
Cancer Heterogeneity, Plasticity and Resistance to Therapies (CANTHER) - UMR 9020 - UMR 1277
Cortot, Alexis B. [Auteur]
Titre de la revue :
Journal of thoracic oncology . official publication of the International Association for the Study of Lung Cancer
Nom court de la revue :
J Thorac Oncol
Date de publication :
2020-03-10
ISSN :
1556-1380
Discipline(s) HAL :
Sciences du Vivant [q-bio]
Résumé en anglais : [en]
Hepatocyte growth factor receptor (MET) tyrosine kinase inhibitors (MET TKIs) have been found to have efficacy against advanced NSCLC with mutations causing MET exon 14 skipping (METex14 mutations), but primary resistance ...
Lire la suite >Hepatocyte growth factor receptor (MET) tyrosine kinase inhibitors (MET TKIs) have been found to have efficacy against advanced NSCLC with mutations causing MET exon 14 skipping (METex14 mutations), but primary resistance seems frequent, as response rates are lower than those for targeted TKIs of other oncogene-addicted NSCLCs. Given the known interplay between MET and phosphoinositide 3-kinases (PI3K), we hypothesized that in METex14 NSCLC, PI3K pathway alterations might contribute to primary resistance to MET TKIs. We reviewed clinical data from 65 patients with METex14 NSCLC, assessing PI3K pathway alterations by targeted next-generation sequencing (mutations) and immunohistochemistry (loss of phosphatase and tensin homolog [PTEN]). Using a cell line derived from a patient with primary resistance to a MET TKI and cell lines harboring both a METex14 mutation and a PI3K pathway alteration, we assessed sensitivity to MET TKIs used alone or with a PI3K inhibitor and investigated relevant signaling pathways. We found a phosphatidylinositol 3-kinase catalytic subunit alpha (PIK3CA) mutation in two of 65 samples (3%) and loss of PTEN in six of 26 samples (23%). All three of the MET TKI-treated patients with a PI3K pathway alteration had been found to have progressive disease at first assessment. Likewise, MET TKIs had no effect on the proliferation of METex14-mutated cell lines with a PI3K pathway alteration, including the PTEN-lacking patient-derived cell line. Treatment combining a MET TKI with a PI3K inhibitor caused inhibition of both PI3K and MAPK signaling and restored sensitivity to MET TKIs. PI3K pathway alterations are common in METex14 NSCLC and may confer primary resistance to MET TKIs. In preclinical models, PI3K inhibition restores sensitivity to MET TKIs.Lire moins >
Lire la suite >Hepatocyte growth factor receptor (MET) tyrosine kinase inhibitors (MET TKIs) have been found to have efficacy against advanced NSCLC with mutations causing MET exon 14 skipping (METex14 mutations), but primary resistance seems frequent, as response rates are lower than those for targeted TKIs of other oncogene-addicted NSCLCs. Given the known interplay between MET and phosphoinositide 3-kinases (PI3K), we hypothesized that in METex14 NSCLC, PI3K pathway alterations might contribute to primary resistance to MET TKIs. We reviewed clinical data from 65 patients with METex14 NSCLC, assessing PI3K pathway alterations by targeted next-generation sequencing (mutations) and immunohistochemistry (loss of phosphatase and tensin homolog [PTEN]). Using a cell line derived from a patient with primary resistance to a MET TKI and cell lines harboring both a METex14 mutation and a PI3K pathway alteration, we assessed sensitivity to MET TKIs used alone or with a PI3K inhibitor and investigated relevant signaling pathways. We found a phosphatidylinositol 3-kinase catalytic subunit alpha (PIK3CA) mutation in two of 65 samples (3%) and loss of PTEN in six of 26 samples (23%). All three of the MET TKI-treated patients with a PI3K pathway alteration had been found to have progressive disease at first assessment. Likewise, MET TKIs had no effect on the proliferation of METex14-mutated cell lines with a PI3K pathway alteration, including the PTEN-lacking patient-derived cell line. Treatment combining a MET TKI with a PI3K inhibitor caused inhibition of both PI3K and MAPK signaling and restored sensitivity to MET TKIs. PI3K pathway alterations are common in METex14 NSCLC and may confer primary resistance to MET TKIs. In preclinical models, PI3K inhibition restores sensitivity to MET TKIs.Lire moins >
Langue :
Anglais
Audience :
Internationale
Vulgarisation :
Non
Établissement(s) :
CNRS
Université de Lille
Université de Lille
Collections :
Date de dépôt :
2021-09-02T07:01:36Z