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Positive feedback between oncogenic KRAS and HIF-1α confers drug resistance in colorectal cancer

Approximately 30%–50% of colorectal cancers (CRCs) harbor the somatic mutated KRAS gene. KRAS G12V, one of the most common KRAS mutations in CRCs, is linked to increased tumor aggressiveness, less response to anti-epidermal growth factor receptor (EGFR) therapy, and poor survival rate. In this study...

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Autores principales: Wang, Yanzhao, Lei, Fuming, Rong, Wanshui, Zeng, Qingmin, Sun, Wenbing
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Dove Medical Press 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4454194/
https://www.ncbi.nlm.nih.gov/pubmed/26060408
http://dx.doi.org/10.2147/OTT.S80017
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author Wang, Yanzhao
Lei, Fuming
Rong, Wanshui
Zeng, Qingmin
Sun, Wenbing
author_facet Wang, Yanzhao
Lei, Fuming
Rong, Wanshui
Zeng, Qingmin
Sun, Wenbing
author_sort Wang, Yanzhao
collection PubMed
description Approximately 30%–50% of colorectal cancers (CRCs) harbor the somatic mutated KRAS gene. KRAS G12V, one of the most common KRAS mutations in CRCs, is linked to increased tumor aggressiveness, less response to anti-epidermal growth factor receptor (EGFR) therapy, and poor survival rate. In this study, we sought to determine whether resistance to EGFR inhibitors in colorectal cancer cells harboring KRAS G12V mutation is associated with hypoxia. Our data indicated that HIF-1α was induced by KRAS G12V signaling at transcription level. Hypoxia or HIF-1α overexpression could increase KRAS G12V activity. Therefore, a positive feedback between hypoxia and KRAS G12V activation was formed. Cetuximab, an EGFR inhibitor, which has a minor effect on KRAS-mutant CRCs, could effectively inhibit the proliferation of CRC cells harboring KRAS G12V mutation when combined with HIF-1α inhibitor PX-478. Our data indicated that hypoxia was involved in resistance to anti-EGFR therapy, and a combination therapy might be necessary for CRC patients with KRAS mutation.
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spelling pubmed-44541942015-06-09 Positive feedback between oncogenic KRAS and HIF-1α confers drug resistance in colorectal cancer Wang, Yanzhao Lei, Fuming Rong, Wanshui Zeng, Qingmin Sun, Wenbing Onco Targets Ther Original Research Approximately 30%–50% of colorectal cancers (CRCs) harbor the somatic mutated KRAS gene. KRAS G12V, one of the most common KRAS mutations in CRCs, is linked to increased tumor aggressiveness, less response to anti-epidermal growth factor receptor (EGFR) therapy, and poor survival rate. In this study, we sought to determine whether resistance to EGFR inhibitors in colorectal cancer cells harboring KRAS G12V mutation is associated with hypoxia. Our data indicated that HIF-1α was induced by KRAS G12V signaling at transcription level. Hypoxia or HIF-1α overexpression could increase KRAS G12V activity. Therefore, a positive feedback between hypoxia and KRAS G12V activation was formed. Cetuximab, an EGFR inhibitor, which has a minor effect on KRAS-mutant CRCs, could effectively inhibit the proliferation of CRC cells harboring KRAS G12V mutation when combined with HIF-1α inhibitor PX-478. Our data indicated that hypoxia was involved in resistance to anti-EGFR therapy, and a combination therapy might be necessary for CRC patients with KRAS mutation. Dove Medical Press 2015-05-26 /pmc/articles/PMC4454194/ /pubmed/26060408 http://dx.doi.org/10.2147/OTT.S80017 Text en © 2015 Wang et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.
spellingShingle Original Research
Wang, Yanzhao
Lei, Fuming
Rong, Wanshui
Zeng, Qingmin
Sun, Wenbing
Positive feedback between oncogenic KRAS and HIF-1α confers drug resistance in colorectal cancer
title Positive feedback between oncogenic KRAS and HIF-1α confers drug resistance in colorectal cancer
title_full Positive feedback between oncogenic KRAS and HIF-1α confers drug resistance in colorectal cancer
title_fullStr Positive feedback between oncogenic KRAS and HIF-1α confers drug resistance in colorectal cancer
title_full_unstemmed Positive feedback between oncogenic KRAS and HIF-1α confers drug resistance in colorectal cancer
title_short Positive feedback between oncogenic KRAS and HIF-1α confers drug resistance in colorectal cancer
title_sort positive feedback between oncogenic kras and hif-1α confers drug resistance in colorectal cancer
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4454194/
https://www.ncbi.nlm.nih.gov/pubmed/26060408
http://dx.doi.org/10.2147/OTT.S80017
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