Targeting MET in Lung Cancer: Will Expectations Finally Be MET?

Abstract

The mesenchymal epithelial transition factor receptor (MET) is a potential therapeutic target in a number of cancers, including non-small cell lung cancer (NSCLC). In NSCLC, MET pathway activation is thought to occur via a diverse set of mechanisms that influence properties affecting cancer cell survival, growth, and invasiveness. Preclinical and clinical evidence suggest a role for MET activation as both a primary oncogenic driver in subsets of lung cancer, and as a secondary driver of acquired resistance to targeted therapy in other genomic subsets. In this review, we explore the biology and clinical significance behind MET exon 14 (METex14) alterations and MET amplification in NSCLC, the role of MET amplification in the setting of acquired resistance to EGFR tyrosine kinase inhibitor therapy in EGFR-mutant NSCLC, and the history of MET pathway inhibitor drug development in NSCLC, highlighting current strategies that enrich for biomarkers that are likely to be predictive of response. While previous trials that focused on MET pathway-directed targeted therapy in unselected or MET overexpressing NSCLC yielded largely negative results, more recent investigations focusing on METex14 alterations and MET amplification have been notable for meaningful clinical responses to MET inhibitor therapy in a substantial proportion of patients.

Co‐expression of EGFR and MET has a synergistic effect on the prognosis of patients with oral squamous cell carcinoma

“…Accordingly, the interaction between EGFR and MET in HNSCC cells may lead to resistance to anti‐EGFR antibodies . Indeed, efforts are underway to define the criteria for optimal use of a combination of MET and EGFR inhibitors wherein MET acts as a targetable co‐driver, particularly in EGFR‐mutant patients . In a study by Yang et al, HGF treatment of OSCC cell lines expressing high EGFR levels induced cetuximab resistance; however, treatment with Met inhibitor PHA‐665752 as well as MET siRNA was able to restore the sensitivity of OSCC cell lines to cetuximab.…”

Circulating Tumor DNA Identifies EGFR Coamplification as a Mechanism of Resistance to Crizotinib in a Patient with Advanced MET-Amplified Lung Adenocarcinoma

“…3 MET amplification has been identified as a relevant molecular alteration in thoracic and upper abdominal cancers. 4–7 Indeed, multiple studies have demonstrated durable responses to MET inhibition among patients with MET -amplified cancers, including patients with CUP. 3,4–7 …”

DNA-Based versus RNA-Based Detection of MET Exon 14 Skipping Events in Lung Cancer

“…[1][2][3][4] These alterations result in exclusion of exon 14 from the MET transcript, thus eliminating the Tyr1003 residue that mediates ubiquitination of the MET gene product hepatocyte growth factor receptor (HGFR). 5,6 As a result, proper degradation of HGFR protein is impaired, leading to enhanced oncogenic signaling. 4,7 Several published case reports have demonstrated clinical responses in patients with lung cancer positive for these variants to HGFR inhibitors (also referred to as MET inhibitors).…”