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Enhancing the Therapeutic Efficacy of KRAS(G12C) Inhibitors in Lung Adenocarcinoma Cell Models by Cotargeting the MAPK Pathway or HSP90
BACKGROUND: KRAS(G12C) inhibitors have shown promising efficacy in early clinical trials, but drug resistance compromises their long-term benefits. Therefore, it is critical to understand the mechanisms of drug resistance and to design appropriate combinatory treatments to improve efficacy. METHODS:...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Hindawi
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8632397/ https://www.ncbi.nlm.nih.gov/pubmed/34858498 http://dx.doi.org/10.1155/2021/2721466 |
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author | Liu, Ying Wu, Lei Lu, Hong Wu, En Ni, Jun Zhou, Xiaorong |
author_facet | Liu, Ying Wu, Lei Lu, Hong Wu, En Ni, Jun Zhou, Xiaorong |
author_sort | Liu, Ying |
collection | PubMed |
description | BACKGROUND: KRAS(G12C) inhibitors have shown promising efficacy in early clinical trials, but drug resistance compromises their long-term benefits. Therefore, it is critical to understand the mechanisms of drug resistance and to design appropriate combinatory treatments to improve efficacy. METHODS: To understand the comprehensive mechanisms of drug resistance, we treated lung cancer cells with KRAS(G12C) inhibitors for different periods and performed transcriptional profiling and signaling analysis to identify critical factors and pathways that drive drug tolerance and resistance. We also evaluated several drug combinations in vitro and in vivo to identify potentially effective therapeutics. RESULTS: We found that the feedback activation of multiple receptor tyrosine kinases (RTKs) may have cooperatively induced intrinsic and adaptive resistance to KRAS(G12C) inhibitors. Notably, continuous KRAS inhibition induced a multidrug-resistant phenotype, implying that upfront combinatory treatment might be required to treat this group of patients. We also demonstrated that concurrently targeting multiple nodes in the RTK/RAS/RAF/MEK/ERK axis improved the efficacy of KRAS(G12C) inhibitors, mainly by suppressing the reactivation of the mitogen-activated protein kinase (MAPK) pathway. Moreover, the combined use of HSP90 and KRAS(G12C) inhibitors effectively induced tumor regression in lung adenocarcinoma models in vitro and in vivo. CONCLUSION: Together, our findings revealed mechanisms underlying KRAS(G12C) inhibitors resistance and provided novel candidate combinatory strategies to improve their anticancer activity. |
format | Online Article Text |
id | pubmed-8632397 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Hindawi |
record_format | MEDLINE/PubMed |
spelling | pubmed-86323972021-12-01 Enhancing the Therapeutic Efficacy of KRAS(G12C) Inhibitors in Lung Adenocarcinoma Cell Models by Cotargeting the MAPK Pathway or HSP90 Liu, Ying Wu, Lei Lu, Hong Wu, En Ni, Jun Zhou, Xiaorong J Oncol Research Article BACKGROUND: KRAS(G12C) inhibitors have shown promising efficacy in early clinical trials, but drug resistance compromises their long-term benefits. Therefore, it is critical to understand the mechanisms of drug resistance and to design appropriate combinatory treatments to improve efficacy. METHODS: To understand the comprehensive mechanisms of drug resistance, we treated lung cancer cells with KRAS(G12C) inhibitors for different periods and performed transcriptional profiling and signaling analysis to identify critical factors and pathways that drive drug tolerance and resistance. We also evaluated several drug combinations in vitro and in vivo to identify potentially effective therapeutics. RESULTS: We found that the feedback activation of multiple receptor tyrosine kinases (RTKs) may have cooperatively induced intrinsic and adaptive resistance to KRAS(G12C) inhibitors. Notably, continuous KRAS inhibition induced a multidrug-resistant phenotype, implying that upfront combinatory treatment might be required to treat this group of patients. We also demonstrated that concurrently targeting multiple nodes in the RTK/RAS/RAF/MEK/ERK axis improved the efficacy of KRAS(G12C) inhibitors, mainly by suppressing the reactivation of the mitogen-activated protein kinase (MAPK) pathway. Moreover, the combined use of HSP90 and KRAS(G12C) inhibitors effectively induced tumor regression in lung adenocarcinoma models in vitro and in vivo. CONCLUSION: Together, our findings revealed mechanisms underlying KRAS(G12C) inhibitors resistance and provided novel candidate combinatory strategies to improve their anticancer activity. Hindawi 2021-11-23 /pmc/articles/PMC8632397/ /pubmed/34858498 http://dx.doi.org/10.1155/2021/2721466 Text en Copyright © 2021 Ying Liu et al. https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Article Liu, Ying Wu, Lei Lu, Hong Wu, En Ni, Jun Zhou, Xiaorong Enhancing the Therapeutic Efficacy of KRAS(G12C) Inhibitors in Lung Adenocarcinoma Cell Models by Cotargeting the MAPK Pathway or HSP90 |
title | Enhancing the Therapeutic Efficacy of KRAS(G12C) Inhibitors in Lung Adenocarcinoma Cell Models by Cotargeting the MAPK Pathway or HSP90 |
title_full | Enhancing the Therapeutic Efficacy of KRAS(G12C) Inhibitors in Lung Adenocarcinoma Cell Models by Cotargeting the MAPK Pathway or HSP90 |
title_fullStr | Enhancing the Therapeutic Efficacy of KRAS(G12C) Inhibitors in Lung Adenocarcinoma Cell Models by Cotargeting the MAPK Pathway or HSP90 |
title_full_unstemmed | Enhancing the Therapeutic Efficacy of KRAS(G12C) Inhibitors in Lung Adenocarcinoma Cell Models by Cotargeting the MAPK Pathway or HSP90 |
title_short | Enhancing the Therapeutic Efficacy of KRAS(G12C) Inhibitors in Lung Adenocarcinoma Cell Models by Cotargeting the MAPK Pathway or HSP90 |
title_sort | enhancing the therapeutic efficacy of kras(g12c) inhibitors in lung adenocarcinoma cell models by cotargeting the mapk pathway or hsp90 |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8632397/ https://www.ncbi.nlm.nih.gov/pubmed/34858498 http://dx.doi.org/10.1155/2021/2721466 |
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