From knowledge to action: The journey toward targeting the MET pathway via MET exon 14 skipping

Targeted therapies have radically altered the prognosis of patients with non–small cell lung cancer (NSCLC). Although the MET pathway was characterized in 1984, the treatment paradigm for patients with MET alterations has only recently changed. Genomic alterations in MET are found in 3%–5% of patients with NSCLC, and can include MET exon 14 (METex14) skipping, MET-activating mutations, and MET amplification. These alterations lead to the prolonged activation of the cellular MET receptor and downstream proliferation pathways that drive cell survival and migration. This review explores the history and pathophysiology of the MET pathway by focusing on METex14 skipping, and highlights insights gained since its discovery. Both unsuccessful and successful treatments that have emerged alongside the evolution of next-generation sequencing are examined, as well as current approved therapies and future options that target potential resistance mechanisms.