Targeting MET amplification in Gastro-oesophageal (GO) malignancies and overcoming MET inhibitor resistance: challenges and opportunities

ABSTRACT

Introduction

MET, the hepatocyte growth factor receptor is amplified in 8% of gastroesophageal (GO) malignancies and associated with poor prognosis. Therapeutic targeting of MET amplification and MET mutations has the potential to improve outcomes for patients with GO cancers (GOC).

Areas covered

The efficacy of MET inhibition (METi) in preclinical studies has yet to translate into meaningful improvements in the treatment paradigm for unselected GOC. MET amplification has been proposed as a superior modality for patient selection; however even if confirmed, frequency and duration of response to METi are limited by rapid activation of primary and secondary resistance pathways. These observations illustrate the challenges inherent in the application of precision oncology predicated on the theory of oncogenic addiction.

Expert opinion

A standardized definition of MET positivity is critical to enhance patient selection. Early successes targeting the METex14 skipping mutation demonstrate the potent therapeutic effects of METi in a clearly molecularly defined cohort. There is robust preclinical rationale and early-phase data supporting exploitation of immune system interaction with MET. Pragmatic investigation of rational therapeutic combinations based on molecular profiling of both primary and metastatic disease sites with sequential circulating tumor DNA analysis can inform successful clinical development of METi agents in GOC.

KEYWORDS:

• MET amplification
• MET inhibition
• oncogenic driver mutations
• targeted therapy

Article highlights

• Early preclinical successes with MET inhibition have not been matched by meaningful clinical benefit in larger scale clinical studies, likely due to poor selection criteria

• Consensus definition of MET positivity is critical to move the field forward and robustly define the target cohort

• Emerging data suggest IHC should be supplemented by FISH analysis; the prevalence of MET amplification in GOC using modern analysis techniques is approximately 8%

• Evaluation for the presence of co-amplified receptor tyrosine kinase inhibitors should be considered

• Further exploration of resistance mechanisms is required to harness the potential of this therapeutic approach

• Targeting the METex14del skipping mutation reinforces the promise of targeting the MET pathways in a stringently and molecularly defined cohort of GO cancers

• Encouraging early-phase data evaluating the role of CLDN 18.2-targeted CAR-T cell therapy demonstrates the potency of this approach and proof of concept data for MET targeted CAR T cells already exists in both breast cancer and mesothelioma

Acknowledgments

The authors would like to acknowledge Anthony Edwards in the illustration department of St James’s Hospital in Dublin for his assistance with Figure 1.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosure

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was notfunded.