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

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 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. A recently identified small molecule shows promise for tackling resistance to a leading colorectal cancer drug. Three proteins that are over-expressed in colorectal cancer are epidermal growth factor receptor (EGFR), RAS and β-catenin. These proteins and their interconnected signaling pathways are therefore important therapeutic targets. EGFR is the target of the drug cetuximab, but many patients are resistant to this drug attributed to mutations in a gene that influences the signaling pathways of the three key proteins. Kang-Yell Choi at Yonsei University in Seoul, South Korea, and co-workers trialed a novel molecular drug on human colorectal cancer tissues and on mice. They confirmed that the new drug leads to reduced EGFR levels by degrading RAS and β-catenin and therefore suppresses the growth of colorectal cancer cells in samples with or without the resistant mutations.