Abstract 3984: Increasing microRNA-378 to enhance sensitivity of EGFR inhibitor in colorectal cancer

Abstract

Colorectal cancer (CRC) is the fourth most frequently diagnosed cancer, more then 40% of patients with CRC have KRAS mutations are resistant to anti-EGFR therapy. Lower expression of microRNA-378 (miR-378) was reported to be associated with CRC contain with KRAS or BRAF mutation when compared with wild type of CRC cells. As known that miR-378 is derived from the 3′-UTR of PGC-1β (Peroxisome proliferator activated receptor gamma coactivator-1β) gene, and expressed abundantly could be stimulated by lauric acid. Therefore, we hypothesized once increase the expression level of miR-378 might restore the sensitivity to anti-EGFR sensitizing of cetuximab in KRAS or BRAF mutated colon cancer cells. Herein, we firstly enhanced expression level of miR-378 in mutants via transfection method, and further treated with cetuximab, hopefully, the mutants re-sensitizing to previously failed therapies could be demonstrated. Seven colon cancer cell lines with confirmed KRAS and BRAF statuses were used in current study. Untreated original cells, cells treated with cetuximab, cells transfected with miR-378, and miR-378 transfected cells combined with cetuximab treatment were included. Cell viabilities were then measured for all, and compared to each other group. Our results showed, after transfected miR-378, although most all of KRAS mutants increased cell viabilities except the BRAF mutated CRC cells; nevertheless, the mutants significantly responsed to cetuximab treatment could be observed when compared to the cells treated with cetuximab only. The results indicated that increased the level of miR-378 combined anti-EGFR drug treatment could lead cell viabilities significantly decreased in either BRAF mutants or 50% of KRAS mutated cells. Obviously, re-sensitized to anti-EGFR drug was coming off following transfected with miR-378 in mutated cells. Based on above findings, we then further tried to use lauric acid (C12:0) to enhance the expression level of miR-378 in the cancer cells, and hopefully it would benefit to those CRC cases who ever failed to anti-EGFR antibody treatment. The similar results showed once enhancing the expression level of miR-378, and then treated with anti-EGFR antibody, consequentially lower cell survival could be observed. Lower protein expression of ERK 1/2 has been also been observed in lauric acid treated CRC cells. All the results tend to disclose lauric acid might be an element, which could trigger KRAS cells restored sensitivity to anti-EGFR based drug. In conclusion, elevating miR-378 expression level in mutated CRC cells by lauric acid, which could be easily derived from olive oil, would allow drug re-sensitization in both BRAF and 50% of KRAS mutated cells, the cells were all significantly suppressed by cetuximab. The role of miR-378 in modulating anti-EGFR sensitivity is obvious; therefore, it was strongly suggested to be a potentially new strategy for the clinical CRC patients who have failed anti-EGFR drug treatment. Note: This abstract was not presented at the meeting. Citation Format: Shih-Chun Bian, Wai-Hung Leung, Yeu-Jye Pang, Yu-Wen Wu, Jing-Jung Chen, Wen-Hui Weng. Increasing microRNA-378 to enhance sensitivity of EGFR inhibitor in colorectal cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3984. doi:10.1158/1538-7445.AM2015-3984