2022 LCRF and MET Crusaders Research Grant on MET-Driven Lung Cancer
Emiliano Cocco, PhD
Miller School of Medicine of the University of Miami
Research Project:
Exploring novel therapeutic options to target MET-driven lung cancers
Summary:
MET alterations are recurrent drivers in Non-Small-Cell lung cancer (NSCLC). While most anti-MET agents are active, resistance develops. Identifying more effective approaches to target MET-driven NSCLCs is an unmet need. Here, we aim to 1) parallel the clinical development of a new anti-MET Antibody-Drug-Conjugate (ADC) with its pre-clinical characterization, 2) evaluate the efficacy of MET inhibitors with different binding modes (type I and II agents) against MET mutant NSCLCs and, 3) unveil mechanisms of resistance to these therapies. Successful completion of this proposal will provide insights into the activity of a new MET ADC, as well as of type I and II MET inhibitors. Moreover, it will reveal possible mechanisms of resistance to these agents, potentially suggesting new therapies.
* * This project was awarded the LCRF William C. Rippe Award for Distinguished Research in Lung Cancer, acknowledging the investigator whose proposal not only demonstrated exceptional scientific merit but also exemplified an enduring commitment to making an impact in the field of lung cancer research.
Updates:
2023:
Dr. Cocco’s work was published in Nature Reviews Clinical Oncology, Feb. 20, 2023.
2025:
The first aim of the project was to preclinically characterize the clinical development of a novel anti-MET agent in resistant MET exon 14 skipping mutation and MET amplified NSCLC models. Human derived cell lines, pre and post treatment, were used, and it was found out that they were molecularly dependent on TRK and MET signaling. A commercially available anti-MET antibody drug conjugate (ADC), ABBV-399, was tested and found to be more active in the resistant model. MET expression is variable in a number of resistant models that were tested suggesting that an anti-MET ADC may be an effective strategy. The second aim was to characterize all MET resistant mutations for their sensitivity to type I and type II MET inhibitors. Through a patient database 4 new MET mutations were identified and evaluated for their sensitivity to MET inhibitors. A manuscript reporting these experiments is under review. For the third aim, cfDNA is being collected from patients being treated in clinical trials with anti-MET ADCS to evaluate the presence of genomic-based resistance.
It is very important to understand the presence and/or development of resistance to treatment so that novel treatment approaches can be identified. MET mutations are important in primary oncogene-driven lung cancers and are also an identified mechanism of resistance to treatment in other oncogene driven lung cancers such as EGFRmut+ and ALK+ NSCLC. ADCs represent a novel treatment that utilizes a targeted approach to the delivery of chemotherapy. It is easy to see how information derived from this research could be very important for the treatment of MET exon 14 skipping mutation NSCLC and for patients with other oncogene-driven cancers who have developed resistance to treatment.