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 β-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 β-catenin and Ras via GSK3β 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 β-catenin and RAS as well as EGFR via targeting the Wnt/β-catenin pathway is a therapeutic strategy for controlling CRC and other types of cancer with aberrantly activated the Wnt/β-catenin and EGFR-RAS pathways, including those with resistance to EGFR-targeting drugs attributed to KRAS mutations.
Bibliographical noteFunding Information:
We thank Drs. B. Vogelstein and K.W. Kinzler for providing the DLD-1 isogenic cells. This study was supported by National Research Foundation of Korea (NRF) grants funded by the Korean government (MSIP) (Grants 2016R1A5A1004694, 2015R1A2A1A05001873). Grant: This study was supported by National Research of Korea (NRF) grants funded by the Korean government (MSIP) (Grants: 2016R1A5A1004694, 2015R1A2A1A05001873) 1Translational Research Center for Protein Function Control, Yonsei University, Seoul, Korea. 2Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea. 3Department of Internal Medicine and Institute of Gastroenterology, College of Medicine, Yonsei University, Seoul, Korea. 4Department of Molecular Biology, College of Natural Science, Pusan National University, Pusan, Korea
All Science Journal Classification (ASJC) codes
- Molecular Medicine
- Molecular Biology
- Clinical Biochemistry