Activating Point Mutations in the MET Kinase Domain Represent a Unique Molecular Subset of Lung Cancer and Other Malignancies Targetable with MET Inhibitors

Biochemistry Genetics Respiratory System Life Sciences Oncology Medicine
MET kinase domain point mutation lung cancer malignancies targeted therapy

This study reveals a new targetable cancer subtype characterized by activating point mutations in the MET tyrosine kinase domain (TKD). Researchers identified MET TKD activating mutations in approximately 0.5% of patients across a genomic data set of over 600,000 cancer cases, encompassing various tumor types, with the highest prevalence in renal cell carcinoma, non-small cell lung cancer (NSCLC), and melanoma.

Through in vitro and animal model studies, they confirmed the oncogenic activity of these mutations and discovered variability in the sensitivity of different mutations to MET inhibitors. Interestingly, some MET TKD mutations were previously identified as site mutations emerging after acquiring resistance to MET inhibitors in MET exon 14 deletion (METex14) NSCLC, but this study found that these mutations can also exist as primary oncogenic driving events.

In two cases of metastatic NSCLC patients with MET TKD mutations (H1094Y and F1200I) and no other known driver genes, researchers observed partial response to treatment with the MET inhibitor elzovantinib, confirming that MET TKD mutations can serve as potential therapeutic targets in NSCLC.

Overall, this study elucidates that MET TKD mutations are a novel oncogenic driving event distributed across various cancers, breaking new ground by expanding MET TKD mutations as therapeutic targets to benefit more cancer patients, thus paving the way for advancements in precision oncology. The study underscores the importance of comprehensive genomic analysis in clinical practice to detect these rare but targetable drivers. This discovery paves the way for future clinical trial designs for this newly recognized molecular cancer subgroup.

A detailed summary of the study’s main contents is provided below:

Introduction:

With the development of precision oncology, the discovery of new targetable genomic variations helps provide selective and effective targeted therapies for more patients. Abnormal MET activation is known to occur through various molecular mechanisms, including MET exon 14 deletion, gene amplification, gene rearrangement, and overexpression. However, MET TKD activating mutations as a potential oncogenic driving mechanism have not been sufficiently recognized and studied.

Study Origin:

This study was a collaboration among authors from several medical institutions, including the Dana-Farber Cancer Institute at Harvard University, Memorial Sloan Kettering Cancer Center, Massachusetts General Hospital in Boston, Georgetown University, Cornell University, and others. The findings were published in the 2024 issue of the journal Cancer Discovery.

Specific Study Content:

1) Distribution and Classification of MET TKD Mutations in Large Cohorts:

  • Researchers analyzed two large cancer cohorts, involving over 600,000 patients, finding that about 0.5% of them carried MET TKD mutations without accompanying METex14 mutations.
  • They classified MET TKD mutations, including stop codons, insertions/deletions, splice site mutations, and missense mutations. Missense mutations were further categorized into oncogenic, potentially oncogenic, and unknown functions based on the OncoKB database annotations.
  • Using three In silico scoring tools (polyphen-2, SIFT, P3DFIKinase) for pathological assessment of missense mutations with unknown functions, they found that about 43% of mutations were predicted to be highly pathogenic or “possibly pathogenic”.
  • MET TKD mutations were most commonly found in renal cell carcinoma, NSCLC, and melanoma.

2) MET TKD Mutations in NSCLC:

  • In NSCLC, the incidence of MET TKD oncogenic/potentially oncogenic mutations was approximately 0.14-0.19%, and they could exist alone or with other driver gene mutations such as KRAS or EGFR.
  • Compared to METex14 mutated NSCLC, patients with MET TKD mutations were older, had a higher smoking history, and had a higher tumor mutation burden.
  • The genomic profile of MET TKD mutated NSCLC was different from METex14 mutations, with higher frequencies of mutations in genes such as TP53 and KEAP1.
  • Two cases of metastatic NSCLC patients with only MET TKD mutations (H1094Y and F1200I) showed partial response to treatment with MET TKI elzovantinib, confirming the potential of these mutations as targets.

3) MET TKD Mutations in Other Tumors:

  • In non-NSCLC tumors, MET TKD oncogenic/potentially oncogenic mutations also had a certain incidence, most commonly in renal cell carcinoma (especially the papillary subtype).
  • In renal cell carcinoma, specific mutation sites such as D1228X and M1250X showed significant enrichment differences compared to NSCLC.

4) Carcinogenic Activity and Sensitivity to MET TKI of MET TKD Mutations in Vitro and Structural Simulation Analysis:

  • Using the Ba/F3 cell line and molecular simulation, researchers confirmed the oncogenic activation of multiple MET TKD mutations (such as H1094Y and F1200I), with some mutations showing differential sensitivity to MET TKI.
  • Structural simulation helped reveal how MET TKD mutations activate the MET signaling pathway by affecting the binding of ATP and small molecule TKIs.

Conclusion:

This study is the first to comprehensively describe MET TKD activating mutations as a novel oncogenic driving mechanism distributed across various cancers. Specifically in NSCLC, these mutations can be effectively targeted by MET TKIs, thereby expanding the beneficiary population of MET-targeted therapies. The study emphasizes the importance of comprehensive genomic analysis in detecting these rare but targetable drivers, providing clear biological and therapeutic evidence for this newly recognized molecular subtype, and will propel the field forward in clinical trials.