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Targeting the ‘Undruggable’ Driver Protein, KRAS, in Epithelial Cancers: Current Perspective

This review summarizes recent development in synthetic drugs and biologics targeting intracellular driver genes in epithelial cancers, focusing on KRAS, and provides a current perspective and potential leads for the field. Compared to biologics, small molecule inhibitors (SMIs) readily penetrate cel...

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Detalles Bibliográficos
Autores principales: Lam, Kuen Kuen, Wong, Siew Heng, Cheah, Peh Yean
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9954350/
https://www.ncbi.nlm.nih.gov/pubmed/36831298
http://dx.doi.org/10.3390/cells12040631
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author Lam, Kuen Kuen
Wong, Siew Heng
Cheah, Peh Yean
author_facet Lam, Kuen Kuen
Wong, Siew Heng
Cheah, Peh Yean
author_sort Lam, Kuen Kuen
collection PubMed
description This review summarizes recent development in synthetic drugs and biologics targeting intracellular driver genes in epithelial cancers, focusing on KRAS, and provides a current perspective and potential leads for the field. Compared to biologics, small molecule inhibitors (SMIs) readily penetrate cells, thus being able to target intracellular proteins. However, SMIs frequently suffer from pleiotropic effects, off-target cytotoxicity and invariably elicit resistance. In contrast, biologics are much larger molecules limited by cellular entry, but if this is surmounted, they may have more specific effects and less therapy-induced resistance. Exciting breakthroughs in the past two years include engineering of non-covalent KRAS G12D-specific inhibitor, probody bispecific antibodies, drug–peptide conjugate as MHC-restricted neoantigen to prompt immune response by T-cells, and success in the adoptive cell therapy front in both breast and pancreatic cancers.
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spelling pubmed-99543502023-02-25 Targeting the ‘Undruggable’ Driver Protein, KRAS, in Epithelial Cancers: Current Perspective Lam, Kuen Kuen Wong, Siew Heng Cheah, Peh Yean Cells Review This review summarizes recent development in synthetic drugs and biologics targeting intracellular driver genes in epithelial cancers, focusing on KRAS, and provides a current perspective and potential leads for the field. Compared to biologics, small molecule inhibitors (SMIs) readily penetrate cells, thus being able to target intracellular proteins. However, SMIs frequently suffer from pleiotropic effects, off-target cytotoxicity and invariably elicit resistance. In contrast, biologics are much larger molecules limited by cellular entry, but if this is surmounted, they may have more specific effects and less therapy-induced resistance. Exciting breakthroughs in the past two years include engineering of non-covalent KRAS G12D-specific inhibitor, probody bispecific antibodies, drug–peptide conjugate as MHC-restricted neoantigen to prompt immune response by T-cells, and success in the adoptive cell therapy front in both breast and pancreatic cancers. MDPI 2023-02-15 /pmc/articles/PMC9954350/ /pubmed/36831298 http://dx.doi.org/10.3390/cells12040631 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Review
Lam, Kuen Kuen
Wong, Siew Heng
Cheah, Peh Yean
Targeting the ‘Undruggable’ Driver Protein, KRAS, in Epithelial Cancers: Current Perspective
title Targeting the ‘Undruggable’ Driver Protein, KRAS, in Epithelial Cancers: Current Perspective
title_full Targeting the ‘Undruggable’ Driver Protein, KRAS, in Epithelial Cancers: Current Perspective
title_fullStr Targeting the ‘Undruggable’ Driver Protein, KRAS, in Epithelial Cancers: Current Perspective
title_full_unstemmed Targeting the ‘Undruggable’ Driver Protein, KRAS, in Epithelial Cancers: Current Perspective
title_short Targeting the ‘Undruggable’ Driver Protein, KRAS, in Epithelial Cancers: Current Perspective
title_sort targeting the ‘undruggable’ driver protein, kras, in epithelial cancers: current perspective
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9954350/
https://www.ncbi.nlm.nih.gov/pubmed/36831298
http://dx.doi.org/10.3390/cells12040631
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