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Targeting mesenchymal-epithelial transition factor signaling in cancer: from genetic alterations to clinical advances and future prospects

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Abstract

The c-Met (mesenchymal-epithelial transition factor) receptor tyrosine kinase, upon activation by its ligand, hepatocyte growth factor (HGF), plays an important role in regulating cellular processes such as proliferation, survival, and metastasis. Dysregulation of c-Met signaling, including overexpression, gene amplification, and mutations, is associated with the development and progression of various cancers, such as non-small cell lung cancer (NSCLC), gastric cancer, and hepatocellular carcinoma. This review explores the oncogenic mechanisms involving c-Met altered cancers, highlighting how dysregulated c-Met signaling promotes tumor growth and metastasis. This work offers a detailed analysis of c-Met expression patterns in different tissues and examines the frequency of c-Met alterations across various cancer types. Advancements in molecular diagnostics have significantly improved the clinical detection of c-Met alterations, facilitating the precise identification of patients eligible for c-Met-targeted therapies. While initial clinical trials of c-Met inhibitors demonstrated promising outcomes, the emergence of resistance remains a major hurdle. This review also covers the mechanisms contributing to resistance, such as secondary mutations, activation of alternative signaling pathways, and tumor cell phenotypic changes. Additionally, it examines current therapeutic approaches targeting c-Met, including small molecule inhibitors, monoclonal antibodies, and combination therapies designed to overcome resistance. The discussion extends to future challenges in c-Met inhibition, highlighting the need for innovative therapeutic strategies and combination regimens to enhance efficacy and mitigate resistance and thus the review emphasizes the transformative potential of c-Met-targeted therapies in advancing cancer treatment.

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Acknowledgements

Namy George, gratefully acknowledges School of Pharmaceutical Sciences, Jaipur National University, Jaipur, India, for academic guidance during her doctoral studies.The authors would like to acknowledge the College of Pharmacy, National University of Science and Technology, Muscat, Oman, for providing the necessary research facilities. This work was supported by The Research Council (TRC) of Oman under the Graduate Research Grant (GRG) program, Grant ID-BFP/GRG/CBS/23/071.

Funding

This work was supported by the College of Pharmacy, National University of Science and Technology, Muscat, Oman. Author Bushara Al Sabahi has received research support from The Research Council (TRC), Oman under the Graduate Research Grant (GRG) program (Grant number BFP/GRG/CBS/23/071).

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Authors and Affiliations

  1. School of Pharmaceutical Sciences, Jaipur National University, Jaipur, Rajasthan, 302017, India

    Namy George & Shalini Bajaj

  2. College of Pharmacy, National University of Science and Technology, PO Box 620, Muscat, PC 130, Oman

    Namy George, Bushra Al Sabahi, Md. Jawaid Akhtar & Shah Alam Khan

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  1. Namy George
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All authors contributed to the study “Targeting c-Met Signaling in Cancer: From MET Alteration to Clinical Advances and Future Prospects”. Material preparation, data collection and analysis were performed by Namy George. The first draft of the manuscript was written by Namy George and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Namy George or Shalini Bajaj.

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George, N., Bajaj, S., Al Sabahi, B. et al. Targeting mesenchymal-epithelial transition factor signaling in cancer: from genetic alterations to clinical advances and future prospects. Mol Biol Rep 52, 1041 (2025). https://doi.org/10.1007/s11033-025-11127-5

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