Cell-Autonomous and Non–Cell-Autonomous Mechanisms of HGF/MET–Driven Resistance to Targeted Therapies: From Basic Research to a Clinical Perspective

Targeted therapies have opened new perspectives in clinical oncology. However, clinicians have observed a lack of response in a relevant percentage of patients and frequent relapse in patients who initially respond. Therefore, a compelling challenge is to identify mechanisms underlying resistance and strategies to circumvent these hurdles. A growing body of evidence indicates that MET, the tyrosine kinase receptor for hepatocyte growth factor (HGF), is frequently implicated in resistance to targeted therapies. In this review, we highlight cell-autonomous and non-cell-autonomous mechanisms through which MET drives resistance, and we discuss some unsolved issues related to the selection of patients who could benefit from combined therapies.