Abstract 5036: Activating MEK1(F129L) mutation as a potential mechanism of acquired resistance to MEK inhibition in human cancers carrying the B-RafV600E mutation
| العنوان: | Abstract 5036: Activating MEK1(F129L) mutation as a potential mechanism of acquired resistance to MEK inhibition in human cancers carrying the B-RafV600E mutation |
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| المؤلفون: | Wen-hui Li, Sherif Daouti, Christine Rizzo, Neal Rosen, Brian Higgins, Huisheng Wang, John Frederick Boylan, Yang Wen, Packman Kathryn E, Huifeng Niu, David C. Heimbrook |
| المصدر: | Cancer Research. 71:5036-5036 |
| بيانات النشر: | American Association for Cancer Research (AACR), 2011. |
| سنة النشر: | 2011 |
| مصطلحات موضوعية: | MAPK/ERK pathway, Genetics, Cancer Research, Mutation, Mutant, Wild type, Cancer, Biology, medicine.disease_cause, medicine.disease, In vitro, Oncology, medicine, Cancer research, Kinase activity, V600E |
| الوصف: | Targeting the Ras/Raf/MEK pathway represents a promising anticancer strategy. The clinical development of MEK inhibitors, similar to other highly selective targeted agents, is expected to have limited durable clinical response due to the emergence of drug acquired resistance. To identify potential mechanisms underlying such resistance, we established MEK inhibitor-resistant clones (HT-29R) from a human colorectal cancer cell line HT-29 harboring the B-Raf V600E mutation. HT-29R are resistant to MEK inhibition under both in vitro and in vivo growth conditions. Drug-induced feedback activation of MEK/ERK and downstream targets were found primarily accountable for the resistance. Moreover, we identified the MEK1(F129L) mutation as a molecular mechanism responsible for pathway activation. In an isogenic cell system and extending into other cancer cell lines, the MEK1(F129L) mutant exhibits higher intrinsic kinase activity than wild type (WT) MEK1, leading to a significant activation of ERK and downstream targets confering resistance to MEK inhibition. The MEK1(F129L) mutation showed stronger binding to c-Raf which suggests an underlying mechanism of the higher kinase activity of the MEK1(F129L). Importantly, the combination of Raf and MEK inhibitors overcame resistance and exhibited greater synergy in HT-29R as compared to HT-29S. This study suggests MEK1 mutation could be a potential mechanism of drug acquired resistance emerging in MEK inhibitor-treated cancer patients and should be monitored in the clinic. Combined inhibition of Raf and MEK represents a potential therapeutic strategy to overcome the resistance. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5036. doi:10.1158/1538-7445.AM2011-5036 |
| تدمد: | 1538-7445 0008-5472 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_________::edc3d4938e0112e00aa687691e13685d https://doi.org/10.1158/1538-7445.am2011-5036 |
| رقم الأكسشن: | edsair.doi...........edc3d4938e0112e00aa687691e13685d |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15387445 00085472 |
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