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Non-genetic adaptive resistance to KRAS(G12C) inhibition: EMT is not the only culprit
Adaptions to therapeutic pressures exerted on cancer cells enable malignant progression of the tumor, culminating in escape from programmed cell death and development of resistant diseases. A common form of cancer adaptation is non-genetic alterations that exploit mechanisms already present in cance...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2022
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9722758/ https://www.ncbi.nlm.nih.gov/pubmed/36483040 http://dx.doi.org/10.3389/fonc.2022.1004669 |
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author | Ning, Wenjuan Marti, Thomas M. Dorn, Patrick Peng, Ren-Wang |
author_facet | Ning, Wenjuan Marti, Thomas M. Dorn, Patrick Peng, Ren-Wang |
author_sort | Ning, Wenjuan |
collection | PubMed |
description | Adaptions to therapeutic pressures exerted on cancer cells enable malignant progression of the tumor, culminating in escape from programmed cell death and development of resistant diseases. A common form of cancer adaptation is non-genetic alterations that exploit mechanisms already present in cancer cells and do not require genetic modifications that can also lead to resistance mechanisms. Epithelial-to-mesenchymal transition (EMT) is one of the most prevalent mechanisms of adaptive drug resistance and resulting cancer treatment failure, driven by epigenetic reprogramming and EMT-specific transcription factors. A recent breakthrough in cancer treatment is the development of KRAS(G12C) inhibitors, which herald a new era of therapy by knocking out a unique substitution of an oncogenic driver. However, these highly selective agents targeting KRAS(G12C), such as FDA-approved sotorasib (AMG510) and adagrasib (MRTX849), inevitably encounter multiple mechanisms of drug resistance. In addition to EMT, cancer cells can hijack or rewire the sophisticated signaling networks that physiologically control cell proliferation, growth, and differentiation to promote malignant cancer cell phenotypes, suggesting that inhibition of multiple interconnected signaling pathways may be required to block tumor progression on KRAS(G12C) inhibitor therapy. Furthermore, the tumor microenvironment (TME) of cancer cells, such as tumor-infiltrating lymphocytes (TILs), contribute significantly to immune escape and tumor progression, suggesting a therapeutic approach that targets not only cancer cells but also the TME. Deciphering and targeting cancer adaptions promises mechanistic insights into tumor pathobiology and improved clinical management of KRAS(G12C)-mutant cancer. This review presents recent advances in non-genetic adaptations leading to resistance to KRAS(G12C) inhibitors, with a focus on oncogenic pathway rewiring, TME, and EMT. |
format | Online Article Text |
id | pubmed-9722758 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-97227582022-12-07 Non-genetic adaptive resistance to KRAS(G12C) inhibition: EMT is not the only culprit Ning, Wenjuan Marti, Thomas M. Dorn, Patrick Peng, Ren-Wang Front Oncol Oncology Adaptions to therapeutic pressures exerted on cancer cells enable malignant progression of the tumor, culminating in escape from programmed cell death and development of resistant diseases. A common form of cancer adaptation is non-genetic alterations that exploit mechanisms already present in cancer cells and do not require genetic modifications that can also lead to resistance mechanisms. Epithelial-to-mesenchymal transition (EMT) is one of the most prevalent mechanisms of adaptive drug resistance and resulting cancer treatment failure, driven by epigenetic reprogramming and EMT-specific transcription factors. A recent breakthrough in cancer treatment is the development of KRAS(G12C) inhibitors, which herald a new era of therapy by knocking out a unique substitution of an oncogenic driver. However, these highly selective agents targeting KRAS(G12C), such as FDA-approved sotorasib (AMG510) and adagrasib (MRTX849), inevitably encounter multiple mechanisms of drug resistance. In addition to EMT, cancer cells can hijack or rewire the sophisticated signaling networks that physiologically control cell proliferation, growth, and differentiation to promote malignant cancer cell phenotypes, suggesting that inhibition of multiple interconnected signaling pathways may be required to block tumor progression on KRAS(G12C) inhibitor therapy. Furthermore, the tumor microenvironment (TME) of cancer cells, such as tumor-infiltrating lymphocytes (TILs), contribute significantly to immune escape and tumor progression, suggesting a therapeutic approach that targets not only cancer cells but also the TME. Deciphering and targeting cancer adaptions promises mechanistic insights into tumor pathobiology and improved clinical management of KRAS(G12C)-mutant cancer. This review presents recent advances in non-genetic adaptations leading to resistance to KRAS(G12C) inhibitors, with a focus on oncogenic pathway rewiring, TME, and EMT. Frontiers Media S.A. 2022-11-22 /pmc/articles/PMC9722758/ /pubmed/36483040 http://dx.doi.org/10.3389/fonc.2022.1004669 Text en Copyright © 2022 Ning, Marti, Dorn and Peng https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Oncology Ning, Wenjuan Marti, Thomas M. Dorn, Patrick Peng, Ren-Wang Non-genetic adaptive resistance to KRAS(G12C) inhibition: EMT is not the only culprit |
title | Non-genetic adaptive resistance to KRAS(G12C) inhibition: EMT is not the only culprit |
title_full | Non-genetic adaptive resistance to KRAS(G12C) inhibition: EMT is not the only culprit |
title_fullStr | Non-genetic adaptive resistance to KRAS(G12C) inhibition: EMT is not the only culprit |
title_full_unstemmed | Non-genetic adaptive resistance to KRAS(G12C) inhibition: EMT is not the only culprit |
title_short | Non-genetic adaptive resistance to KRAS(G12C) inhibition: EMT is not the only culprit |
title_sort | non-genetic adaptive resistance to kras(g12c) inhibition: emt is not the only culprit |
topic | Oncology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9722758/ https://www.ncbi.nlm.nih.gov/pubmed/36483040 http://dx.doi.org/10.3389/fonc.2022.1004669 |
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