Savolitinib in NSCLC: progress in the MET exon 14 journey
Mené en Chine sur 87 patients atteints d'un cancer du poumon non à petites cellules, de stade localement avancé ou métastatique et avec mutation du gène MET (perte de l’exon 14 ; âge médian : 70 ans), cet essai multicentrique de phase IIIB évalue l'efficacité, du point de vue du taux de réponse objective, et la toxicité du savolitinib en traitement de première ligne
Under normal physiological conditions, MET receptor tyrosine kinase is activated by its ligand, hepatocyte growth factor, activating various downstream pathways essential for embryogenesis, organogenesis, cell proliferation, and cell motility.1,2 In human cancers, MET is activated by various genetic mechanisms, including point mutations, fusions, and amplifications.1,2 Among these processes, the MET exon 14 skipping mutation is a unique MET activation mechanism occurring mainly in non-small-cell lung cancer (NSCLC). This mutation disrupts splice consensus sequences, such as the acceptor site, donor site, branch site, or polypyrimidine tract, which are essential for precise mRNA splicing, resulting in direct binding of exon 13 to exon 15 with a loss of exon 14.1,2 Because MET exon 14 encodes the domain containing tyrosine 1003, which is a binding site for c-CBL E3 ligase, its skipping prevents ubiquitination and proteasome degradation, leading to MET accumulation, which is believed to be the activation mechanism.2 Similarly, missense mutation of tyrosine 1003 confers transforming properties, albeit rare.2 MET exon 14 skipping mutations occur in approximately 3% of NSCLC cases, making these tumours sensitive to small-molecule MET inhibitors