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Published on: July 21, 2018
Tracking MET de-addiction in lung cancer: A road towards the oncogenic target
S Pilotto1, L Carbognin1, N Karachaliou2
1Medical Oncology, University of Verona, Azienda Ospedaliera Universitaria Integrata, Verona, Italy.
Abstract:
The discovery of druggable oncogenic drivers (i.e. EGFR and ALK), along with the introduction of comprehensive tumor genotyping techniques into the daily clinical practice define non-small-cell lung cancer (NSCLC) asa group of heterogeneous diseases, requiring a context-personalized clinico-therapeutical approach. Among the most investigated biomarkers, the MET proto-oncogene has been extensively demonstrated to play a crucial role throughout the lung oncogenesis, unbalancing the proliferation/apoptosis signaling and influencing the epithelial-mesenchymal transition and the invasive phenotype. Nevertheless, although different mechanisms eliciting the aberrant MET-associated oncogenic stimulus have been detected in lung cancer (such as gene amplification, increased gene copy number, mutations and MET/HGF overexpression), to date no clinically impactful results have been achieved with anti-MET tyrosine kinase inhibitors and monoclonal antibodies in the context of an unselected or MET enriched population. Recently, MET exon 14 splicing abnormalities have been identified asa potential oncogenic target in lung cancer, able to drive the activity of MET inhibitors in molecularly selected patients. In this paper, the major advancement and drawbacks of MET history in lung cancer are reviewed, underlying the renewed scientific euphoria related to the recent identification of MET exon 14 splicing variants asan actionable oncogenic target.
Insights
MET exon 14 splicing abnormalities represent a promising target in non-small cell lung cancer (NSCLC). This review highlights advancements and challenges in targeting MET for personalized NSCLC treatment strategies.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Non-small cell lung cancer (NSCLC) is a heterogeneous disease requiring personalized treatment approaches.
- Druggable oncogenic drivers like EGFR and ALK have been identified, alongside advanced tumor genotyping techniques.
- The MET proto-oncogene is crucial in lung oncogenesis, affecting proliferation, apoptosis, and epithelial-mesenchymal transition.
Purpose of the Study:
- To review the historical advancements and drawbacks of targeting MET in lung cancer.
- To highlight the recent identification of MET exon 14 splicing variants as an actionable target.
- To discuss the potential of MET inhibitors in molecularly selected NSCLC patients.
Main Methods:
- Literature review of studies on MET proto-oncogene in lung cancer.
- Analysis of different mechanisms of aberrant MET activation (amplification, mutations, overexpression).
- Evaluation of clinical outcomes with anti-MET therapies in unselected and enriched populations.
Main Results:
- Despite various MET alterations, anti-MET therapies have shown limited clinical impact in unselected populations.
- MET exon 14 splicing abnormalities have emerged as a key oncogenic driver in a subset of NSCLC patients.
- This specific alteration enables targeted therapy with MET inhibitors in molecularly selected patients.
Conclusions:
- MET exon 14 splicing variants represent a significant breakthrough in personalized NSCLC therapy.
- Targeting MET exon 14 splicing abnormalities offers renewed hope for effective treatment in selected NSCLC patients.
- Further research and clinical trials are warranted to optimize MET-targeted strategies in NSCLC.
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