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Abstract: Lung cancer is one of the most frequent cancers in the world with a high mortality rate. The discovery of oncogenic alterations in these cancers allowed the development of targeted therapies against several receptor tyrosine kinases (RTK) including EGFR, ALK or MET and contributed to improve the prognosis of some patients. Mutations impacting the MET receptor exon 14 splice sites (METex14) have recently been detected in about 3% of lung cancers and lead to the loss of the juxtamembrane domain with several negative regulatory sites. METex14 does not lead to constitutive activation of the receptor but we demonstrated that HGF, its ligand, is required for the full development of the transforming capabilities of the METex14 receptor in SCID-HGFhuman transgenic mice.
Several clinical trials have shown that only half of METex14 patients responded to MET inhibitors. While encouraging, these results are lower than those obtained with other treatments such as EGFR inhibitors. Interestingly, METex14 mutations are frequently associated with other molecular alterations including PTEN loss or TP53 mutations. Furthermore, we have shown that many METex14 mutated patients have autocrine secretion of HGF ligand. Understanding how these co-alterations impact METex14 oncogenicity and sensitivity to existing therapies is of outmost importance to identify patients that could benefit from them.
Frampton et al., 2015, Cancer Discov. – Togashi et al., 2015, Lung Cancer – Wolf et al., 2020, NEJM