Abstract 911: Targeting the mutant KRAS/BRAF-induced enhancer as an approach to overcome resistance to 5-fluorouracil-based chemotherapy in colorectal cancer

Autor: Zhiquan Wang, Erin E. Tapper, Qian Nie, Phillip A. Kubica, Steven M. Offer, Kelly J. Bouchonville, Colbren S. Trogstad-Isaacson, Calvin R. Jerde, Shikshya Shrestha, Rentian Wu, Robert B. Diasio
Rok vydání: 2018
Předmět:
Zdroj: Cancer Research. 78:911-911
ISSN: 1538-7445
0008-5472
Popis: Colorectal cancer (CRC) is the third most common cancer and is expected to cause approximately 50,000 deaths in the US in 2017. The antimetabolite 5-fluorouracil (5-FU) is the cornerstone of first-line adjuvant chemotherapy regimens for CRC. Resistance to 5-FU-based chemotherapies develops over time and is the greatest obstacle to effective management in this disease. However, the resistance mechanisms of 5-FU are largely unknown. Approximately 50% of the CRC cases have activating mutations in KRAS or BRAF. Based on recent clinical data, it is now appreciated that KRAS/BRAF mutations are associated with worse survival in 5-FU-based chemotherapies for CRC. Therefore, there is an urgent unmet need for improved therapeutic options to treat mutant KRAS/BRAF tumors. We analyzed the differential activation status of enhancers in KRAS/BRAF mutant and wildtype CRC cell lines. Enhancers that associated with genes regulating pyrimidine metabolism were significantly enriched in KRAS/BRAF mutant CRC cells. Among them, the differential activation of an enhancer located ~400kb upstream of the DPYD promoter was most significant. By using CRISPR-dCas9 system, specifically targeting of p300 to the enhancer significantly increased DPYD expression, and Ezh2 significantly decreased expression. Knockout (KO) of this enhancer resulted in reductions in DPD expression and increased resistance to 5-FU. In mouse xenograft studies, enhancer-KO cells responded to doses of 5-FU that were otherwise ineffective against control cells. Treating KRAS mutant CRC cells with CBP30, H3K27 acetyl-transferase inhibitor, significantly reduced DPYD expression. Synergistic interactions was identified between CBP30 and 5-FU. Finally, mouse xenograft studies strongly suggest that inhibition of H3K27ac may significantly improve 5-FU effectiveness against KRAS mutant tumors. In summary, the present studies advance our understanding of how mutant KRAS/BRAF epigenetically regulates DPYD expression and results in 5-FU resistance in CRC. We showed that clinical treatment of CRC might be significantly improved by the development of future pharmacologic approaches targeting enhancers that are activated by mutant KRAS/BRAF. Citation Format: Rentian Wu, Qian Nie, Phillip A. Kubica, Zhiquan Wang, Shikshya Shrestha, Colbren S. Trogstad-Isaacson, Calvin R. Jerde, Erin E. Tapper, Kelly J. Bouchonville, Steven M. Offer, Robert B. Diasio. Targeting the mutant KRAS/BRAF-induced enhancer as an approach to overcome resistance to 5-fluorouracil-based chemotherapy in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 911.
Databáze: OpenAIRE
Externí odkaz: