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

Sang-Kyu Lee,Do Sik Min,Eun Ji Ro,Pu-Hyeon Cha,Yong-Hee Cho,Kang-Yell Choi,Jieun Park,Woo-Jeong Jeong,Hyuntae Kim,Jeong-Soo Yoon,Gyoonhee Han,Tae Il Kim

doi:10.1038/s12276-018-0182-2

Sang-Kyu Lee, Do Sik Min + Show 10 more

Open Access

https://doi.org/10.1038/s12276-018-0182-2

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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.

Highlights

Introduction TheWnt/β-catenin and RAS/extracellular signalregulated kinase (ERK) pathways play important roles in the regulation of various cellular events, including proliferation, differentiation, and transformation
Given that both β-catenin and RAS are stabilized in colorectal cancer (CRC) patient tissues mostly having adenomatous polyposis coli (APC) mutations and that epidermal growth factor receptor (EGFR) is a transcriptional target of the Wnt/β-catenin pathway, we tested whether expression levels of β-catenin, RAS, and EGFR are correlated in CRC patient tissues
EGFR is overexpressed in human CRC and plays a role in synergistic tumorigenesis[14]

Summary

Introduction

Introduction TheWnt/β-catenin and RAS/extracellular signalregulated kinase (ERK) pathways play important roles in the regulation of various cellular events, including proliferation, differentiation, and transformation. Mutations in genes in both pathways, such as adenomatous polyposis coli (APC) and KRAS, which occur in as many as 90% and in 40–50%1,2, respectively, of human colorectal cancers (CRCs), are known to be involved in the initiation and progression of CRC. Both APC and KRAS mutations synergistically promote cellular transformation and tumor growth[3,4,5], which is attributed to the activation of the RAS-ERK pathway via the aberrant activation of the Wnt/ β-catenin signaling caused the loss of APC6–8. Therapies targeting both the Wnt/β-catenin and EGFR-RAS-ERK pathways, especially those lowering

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