MET Exon 14-altered Lung Cancers and MET Inhibitor Resistance

MET tyrosine kinase inhibitors (TKIs) can achieve modest clinical outcomes in exon 14-altered lung cancers, likely secondary to primary resistance. Mechanisms of primary resistance remain poorly characterized and comprehensive proteomic analyses have not previously been performed. We performed hybri...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:Clinical cancer research 2021-02, Vol.27 (3), p.799-806
Hauptverfasser: Guo, Robin, Offin, Michael, Brannon, A Rose, Chang, Jason, Chow, Andrew, Delasos, Lukas, Girshman, Jeffrey, Wilkins, Olivia, McCarthy, Caroline G, Makhnin, Alex, Falcon, Christina, Scott, Kerry, Tian, Yuan, Cecchi, Fabiola, Hembrough, Todd, Alex, Deepu, Shen, Ronglai, Benayed, Ryma, Li, Bob T, Rudin, Charles M, Kris, Mark G, Arcila, Maria E, Rekhtman, Natasha, Paik, Paul, Zehir, Ahmet, Drilon, Alexander
Format: Artikel
Sprache:eng
Schlagworte:
Online-Zugang:Volltext
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
Beschreibung
Zusammenfassung:MET tyrosine kinase inhibitors (TKIs) can achieve modest clinical outcomes in exon 14-altered lung cancers, likely secondary to primary resistance. Mechanisms of primary resistance remain poorly characterized and comprehensive proteomic analyses have not previously been performed. We performed hybrid capture-based DNA sequencing, targeted RNA sequencing, cell-free DNA sequencing, selected reaction monitoring mass spectrometry (SRM-MS), and immunohistochemistry on patient samples of exon 14-altered lung cancers treated with a MET TKI. Associations between overall response rate (ORR), progression-free survival (PFS), and putative genomic alterations and MET protein expression were evaluated. Seventy-five of 168 exon 14-altered lung cancers received a MET TKI. Previously undescribed (zygosity, clonality, whole-genome duplication) and known (copy-number focality, tumor mutational burden, mutation region/type) genomic factors were not associated with ORR/PFS ( > 0.05). In contrast, MET expression was associated with MET TKI benefit. Only cases with detectable MET expression by SRM-MS ( = 15) or immunochemistry ( = 22) responded to MET TKI therapy, and cancers with H-score ≥ 200 had a higher PFS than cancers below this cutoff (10.4 vs. 5.5 months, respectively; HR, 3.87; = 0.02). In exon 14-altered cancers treated with a MET TKI, a comprehensive analysis of previously unknown and known genomic factors did not identify a genomic mechanism of primary resistance. Instead, MET expression correlated with benefit, suggesting the potential role of interrogating the proteome in addition to the genome in confirmatory prospective trials.
ISSN:1078-0432
1557-3265
DOI:10.1158/1078-0432.CCR-20-2861