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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...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2023
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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. |
format | Online Article Text |
id | pubmed-9954350 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
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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