The molecular characterisation of MET addiction in lung cancer

Abstract

The traditional classification of lung cancer has been radically altered with increased understanding of the molecular alterations and genomic biomarkers that drive the development of the disease. Whilst molecularly targeted therapies, and immunotherapy agents, have transformed NSCLC treatment in recent years, only a subset of patients respond to these treatments, and there remains a pressing need for treatment alternatives in the majority of patients. The large-scale profiling of lung cancer genomes has allowed for the identification of a number of novel therapeutic targets, and, MET, the tyrosine kinase hepatocyte growth factor (HGF) receptor, has emerged as an attractive candidate. Clinical studies on MET-targeting cancer therapies, however, have produced mixed results, and MET-relevant predictive biomarkers remain elusive. This has led to some pessimism about the role of MET in the pathogenesis of NSCLC and the validity of MET as a targetable oncogenic driver. The identification of MET exon 14 (METex14) splicing alterations in recent years, however, and the subsequent clinical successes treating NSCLC patients with these alterations, has led to renewed enthusiasm. In this thesis, potential causes for the failure of MET TKIs in the clinic to date are explored, and the potential of MET as a primary oncogenic driver in lung cancer is discussed. An over-looked resistance mechanism to MET TKIs in MET-amplified NSCLC patients is investigated, and the possible molecular basis behind this resistance is discussed. We demonstrate a number of strategies developed to overcome HGF-induced resistance to MET TKIs in MET-amplified NSCLC, and also present data involving a novel target in MET-driven cancer. Finally, we look to the future, and discuss clinical trial design in MET-driven lung cancer. Our ultimate aim: to treat molecularly selected NSCLC patients with true MET-positive disease, using the appropriate MET targeting drug or drug combination in an appropriately designed clinical trial.