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http://dx.doi.org/10.1038/s12276-018-0182-2

A small molecule approach to degrade RAS with EGFR repression is a potential therapy for KRAS mutation-driven colorectal cancer resistance to cetuximab  

Lee, Sang-Kyu (Translational Research Center for Protein Function Control, Yonsei University)
Cho, Yong-Hee (Translational Research Center for Protein Function Control, Yonsei University)
Cha, Pu-Hyeon (Translational Research Center for Protein Function Control, Yonsei University)
Yoon, Jeong-Soo (Translational Research Center for Protein Function Control, Yonsei University)
Ro, Eun Ji (Translational Research Center for Protein Function Control, Yonsei University)
Jeong, Woo-Jeong (Translational Research Center for Protein Function Control, Yonsei University)
Park, Jieun (Translational Research Center for Protein Function Control, Yonsei University)
Kim, Hyuntae (Translational Research Center for Protein Function Control, Yonsei University)
Kim, Tae Il (Department of Internal Medicine and Institute of Gastroenterology, College of Medicine, Yonsei University)
Min, Do Sik (Translational Research Center for Protein Function Control, Yonsei University)
Han, Gyoonhee (Translational Research Center for Protein Function Control, Yonsei University)
Choi, Kang-Yell (Translational Research Center for Protein Function Control, Yonsei University)
Publication Information
Experimental and Molecular Medicine / v.50, no.11, 2018 , pp. 12.1-12.12 More about this Journal
Abstract
Drugs targeting the epidermal growth factor receptor (EGFR), such as cetuximab and panitumumab, have been prescribed for metastatic colorectal cancer (CRC), but patients harboring KRAS mutations are insensitive to them and do not have an alternative drug to overcome the problem. The levels of ${\beta}$-catenin, EGFR, and RAS, especially mutant KRAS, are increased in CRC patient tissues due to mutations of adenomatous polyposis coli (APC), which occur in 90% of human CRCs. The increases in these proteins by APC loss synergistically promote tumorigenesis. Therefore, we tested KYA1797K, a recently identified small molecule that degrades both ${\beta}$-catenin and Ras via $GSK3{\beta}$ activation, and its capability to suppress the cetuximab resistance of KRAS-mutated CRC cells. KYA1797K suppressed the growth of tumor xenografts induced by CRC cells as well as tumor organoids derived from CRC patients having both APC and KRAS mutations. Lowering the levels of both ${\beta}$-catenin and RAS as well as EGFR via targeting the $Wnt/{\beta}$-catenin pathway is a therapeutic strategy for controlling CRC and other types of cancer with aberrantly activated the $Wnt/{\beta}$-catenin and EGFR-RAS pathways, including those with resistance to EGFR-targeting drugs attributed to KRAS mutations.
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