Elsevier

Cancer Treatment Reviews

Volume 66, May 2018, Pages 95-103
Cancer Treatment Reviews

Anti-Tumour Treatment
Untying the gordion knot of targeting MET in cancer

https://doi.org/10.1016/j.ctrv.2018.04.008Get rights and content

Highlights

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    Aberrant MET signaling promotes tumor growth, invasion, metastasis and survival.

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    Activated MET pathway is implicated in acquired resistance to targeted therapies.

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    Early trials targeting MET failed due to poor biomarker and patient selection.

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    MET amplification and mutation are evolving as predictors for MET inhibition.

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    Trials using novel MET inhibitors in biomarker selected population are needed.

Abstract

Despite compelling evidence backing the crucial role of a dysregulated MET axis in cancer and a myriad of agents targeting this pathway in active clinical development, the therapeutic value of MET inhibition in cancer oncology remains to be established. Although a series of disappointing clinical trials, at first, lessened fervor for targeting this pathway, investigations continue unabated with a number of novel active compounds entering clinical trials. Suboptimal designs which lacked biomarker selection have been the main reason for these early failures and this has stimulated a more biomarker enriched approach lately. Fresh insights into the mechanics of diverse MET aberrations (amplifications and mutations) have allowed trial enrichment for appropriate patients in appropriate disease settings. Development of MET inhibition as a therapeutic strategy in cancer has been a lesson in itself reflecting the challenging opportunities enclosed in the genetic landscape of cancer. Here, we will review the status of MET targeted therapy in development as it stands today, discuss emerging paradigms in MET inhibition and theorize on concepts for future development. We venture to propose that in spite of early disappointments, the future of this therapeutic strategy is promising with use of appropriate predictive biomarker in the right clinical context.

Section snippets

Overview of MET axis

MET proto-oncogene on chromosome 7q31 encodes a receptor tyrosine kinase which coupled with its ligand, HGF (hepatocyte growth factor), activates several downstream pathways that promote tumor growth, survival, and angiogenesis (Fig. 1) [1]. Additionally, this signaling can rework cytoskeletal framework and adhesions, triggering cellular morphogenesis and motility necessary for tumor invasion, migration and metastasis [1]. Through extensive functional cross-talk, MET can also mediate resistance

Road travelled thus far

Failure of randomized phase 2 study of MET antibody, Onartuzumab (Genentech) combined with erlotinib in patients with advanced non-small-cell lung cancer (NSCLC) was the first of these unsuccessful attempts [5]. The premise was that MET inhibition will overcome acquired resistance to targeting epidermal growth factor receptor (EGFR), but no improvement in progression-free survival (PFS) or overall survival (OS) was seen. Notably, the study did not require any biomarker selection. However, both

Lessons learned

One clear miscalculation in most of these studies was an unselected population. The other common theme was use of protein overexpression by IHC as a biomarker either for selection strategy or for post-hoc assessment of efficacy. The attraction of IHC is understandable. It is relatively inexpensive, readily available, and most importantly a high prevalence biomarker in most cancers. There are however two major caveats with this strategy. Firstly, given that MET expression is seen in normal

Search for the optimal biomarker

To date, MET trials have used protein expression by IHC as a biomarker for selection. The success of IHC as a feasible and effective biomarker is evident from the experience with hormone receptor positive breast cancer. However, in other cases, presence of protein expression, such as HER2 in gastric cancer, does not sufficiently predict efficacy of anti-HER2 therapy [28]. Early studies have demonstrated the limited ability of MET protein expression in predicting efficacy of anti-MET therapies.

Alchemy of MET inhibitors

The ideal MET inhibitor should be a high potency antagonist; both of ligand-dependent and ligand-independent MET signaling without any agonist activity. There have been some shortcomings in earlier generation of MET inhibitors. Firstly, although in theory, HGF antibodies, such as Rilotumumab, can inhibit MET by neutralizing ligand–receptor interaction, they may not be effective in cases of where activation of the axis occurs in a ligand-independent fashion, such as MET amplifications or

Challenges of patient selection

Selecting the right drug and right biomarker is almost as crucial as selecting the right clinical setting. Therefore the next tier of questioning that ensues is whether MET inhibition, in and of itself, will be sufficient to improve clinical responses, whether innate/acquired mechanisms of resistance can blunt this effect and whether co-targeting these pathways will be more effective.

The success of targeting MET relies heavily on the dependence of tumors on the MET pathway for survival,

Conclusions

In spite of extensive pre-clinical data and abundance of therapeutic agents, developing a successful clinical trial targeting MET has eluded us. There are three core reasons behind this subpar progress. Firstly, although dysregulation of MET signaling is common in diverse tumor types the relative importance of these alterations (overexpression vs. mutations vs. amplifications) in tumor biology is largely unknown. Defining this would be a significant factor in selecting appropriate biomarker in

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Conflicts of interest

No conflicts of interest.

Financial support

No financial disclosures.

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