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Oncogenic mechanism-based pharmaceutical validation of therapeutics targeting MET receptor tyrosine kinase

Aberrant expression and/or activation of the MET receptor tyrosine kinase is characterized by genomic recombination, gene amplification, activating mutation, alternative exon-splicing, increased transcription, and their different combinations. These dysregulations serve as oncogenic determinants con...

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Autores principales: Yao, Hang-Ping, Tong, Xiang-Min, Wang, Ming-Hai
Formato: Online Artículo Texto
Lenguaje:English
Publicado: SAGE Publications 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8020248/
https://www.ncbi.nlm.nih.gov/pubmed/33868463
http://dx.doi.org/10.1177/17588359211006957
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author Yao, Hang-Ping
Tong, Xiang-Min
Wang, Ming-Hai
author_facet Yao, Hang-Ping
Tong, Xiang-Min
Wang, Ming-Hai
author_sort Yao, Hang-Ping
collection PubMed
description Aberrant expression and/or activation of the MET receptor tyrosine kinase is characterized by genomic recombination, gene amplification, activating mutation, alternative exon-splicing, increased transcription, and their different combinations. These dysregulations serve as oncogenic determinants contributing to cancerous initiation, progression, malignancy, and stemness. Moreover, integration of the MET pathway into the cellular signaling network as an addiction mechanism for survival has made this receptor an attractive pharmaceutical target for oncological intervention. For the last 20 years, MET-targeting small-molecule kinase inhibitors (SMKIs), conventional therapeutic monoclonal antibodies (TMABs), and antibody-based biotherapeutics such as bispecific antibodies, antibody–drug conjugates (ADC), and dual-targeting ADCs have been under intensive investigation. Outcomes from preclinical studies and clinical trials are mixed with certain successes but also various setbacks. Due to the complex nature of MET dysregulation with multiple facets and underlying mechanisms, mechanism-based validation of MET-targeting therapeutics is crucial for the selection and validation of lead candidates for clinical trials. In this review, we discuss the importance of various types of mechanism-based pharmaceutical models in evaluation of different types of MET-targeting therapeutics. The advantages and disadvantages of these mechanism-based strategies for SMKIs, conventional TMABs, and antibody-based biotherapeutics are analyzed. The demand for establishing new strategies suitable for validating novel biotherapeutics is also discussed. The information summarized should provide a pharmaceutical guideline for selection and validation of MET-targeting therapeutics for clinical application in the future.
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spelling pubmed-80202482021-04-16 Oncogenic mechanism-based pharmaceutical validation of therapeutics targeting MET receptor tyrosine kinase Yao, Hang-Ping Tong, Xiang-Min Wang, Ming-Hai Ther Adv Med Oncol Review Aberrant expression and/or activation of the MET receptor tyrosine kinase is characterized by genomic recombination, gene amplification, activating mutation, alternative exon-splicing, increased transcription, and their different combinations. These dysregulations serve as oncogenic determinants contributing to cancerous initiation, progression, malignancy, and stemness. Moreover, integration of the MET pathway into the cellular signaling network as an addiction mechanism for survival has made this receptor an attractive pharmaceutical target for oncological intervention. For the last 20 years, MET-targeting small-molecule kinase inhibitors (SMKIs), conventional therapeutic monoclonal antibodies (TMABs), and antibody-based biotherapeutics such as bispecific antibodies, antibody–drug conjugates (ADC), and dual-targeting ADCs have been under intensive investigation. Outcomes from preclinical studies and clinical trials are mixed with certain successes but also various setbacks. Due to the complex nature of MET dysregulation with multiple facets and underlying mechanisms, mechanism-based validation of MET-targeting therapeutics is crucial for the selection and validation of lead candidates for clinical trials. In this review, we discuss the importance of various types of mechanism-based pharmaceutical models in evaluation of different types of MET-targeting therapeutics. The advantages and disadvantages of these mechanism-based strategies for SMKIs, conventional TMABs, and antibody-based biotherapeutics are analyzed. The demand for establishing new strategies suitable for validating novel biotherapeutics is also discussed. The information summarized should provide a pharmaceutical guideline for selection and validation of MET-targeting therapeutics for clinical application in the future. SAGE Publications 2021-04-03 /pmc/articles/PMC8020248/ /pubmed/33868463 http://dx.doi.org/10.1177/17588359211006957 Text en © The Author(s), 2021 https://creativecommons.org/licenses/by-nc/4.0/ This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).
spellingShingle Review
Yao, Hang-Ping
Tong, Xiang-Min
Wang, Ming-Hai
Oncogenic mechanism-based pharmaceutical validation of therapeutics targeting MET receptor tyrosine kinase
title Oncogenic mechanism-based pharmaceutical validation of therapeutics targeting MET receptor tyrosine kinase
title_full Oncogenic mechanism-based pharmaceutical validation of therapeutics targeting MET receptor tyrosine kinase
title_fullStr Oncogenic mechanism-based pharmaceutical validation of therapeutics targeting MET receptor tyrosine kinase
title_full_unstemmed Oncogenic mechanism-based pharmaceutical validation of therapeutics targeting MET receptor tyrosine kinase
title_short Oncogenic mechanism-based pharmaceutical validation of therapeutics targeting MET receptor tyrosine kinase
title_sort oncogenic mechanism-based pharmaceutical validation of therapeutics targeting met receptor tyrosine kinase
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8020248/
https://www.ncbi.nlm.nih.gov/pubmed/33868463
http://dx.doi.org/10.1177/17588359211006957
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