BMP4 and PHLDA1 are plausible drug-targetable candidate genes for KRAS G12A-, G12D-, and G12V-driven colorectal cancer

Shumpei Ohnami,Keiichi Ohshima,Akane Naruoka,Masatoshi Kusuhara,Keiichi Hatakeyama,Yu Takahashi,Hiroyasu Kagawa,Fukumi Kamada,Kai Chen,Kenichi Urakami,Ken Yamaguchi,Yuji Shimoda,Sumiko Ohnami,Ai Sakai,Yasuto Akiyama,Sou Nakatani,Takeshi Nagashima,Akio Shiomi,Kouji Maruyama

doi:10.1007/s11010-021-04172-8

Shumpei Ohnami, Keiichi Ohshima + Show 17 more

Open Access

https://doi.org/10.1007/s11010-021-04172-8

Copy DOI

Abstract

Despite the frequent detection of KRAS driver mutations in patients with colorectal cancer (CRC), no effective treatments that target mutant KRAS proteins have been introduced into clinical practice. In this study, we identified potential effector molecules, based on differences in gene expression between CRC patients carrying wild-type KRAS (n = 390) and those carrying KRAS mutations in codon 12 (n = 240). CRC patients with wild-type KRAS harboring mutations in HRAS, NRAS, PIK3CA, PIK3CD, PIK3CG, RALGDS, BRAF, or ARAF were excluded from the analysis. At least 11 promising candidate molecules showed greater than two-fold change between the KRAS G12 mutant and wild-type and had a Benjamini-Hochberg-adjusted P value of less than 1E-08, evidence of significantly differential expression between these two groups. Among these 11 genes examined in cell lines transfected with KRAS G12 mutants, BMP4, PHLDA1, and GJB5 showed significantly higher expression level in KRAS G12A, G12D, and G12V transfected cells than in the wild-type transfected cells. We expect that this study will lead to the development of novel treatments that target signaling molecules functioning with KRAS G12-driven CRC.

Highlights

The incidence and mortality rates of colorectal cancer (CRC) have recently been increasing in Japan [1]
Advanced CRC is typically treated with monoclonal antibodies targeting epidermal growth factor receptor (EGFR), such as cetuximab or panitumumab, used alone or in combination with standard chemotherapy, but CRC patients harboring KRAS mutations do not respond to the antibodybased anti-EGFR treatment [4]
KRAS mutations were detected in 41.0% of all cases (372/906), which was consistent with the frequencies for these mutations observed in previous studies [35]

Summary

Introduction

The incidence and mortality rates of colorectal cancer (CRC) have recently been increasing in Japan [1]. Surgical resections can cure CRC in the early stage, and advances in pharmacotherapy have improved the treatment outcomes in patients with unresectable and advanced/recurrent-stage CRC. The five-year survival rate in patients with advanced stage IV CRC is quite low at approximately 18% [2]. New therapeutic drugs, molecular targeted agents with fewer adverse drug reactions, need to be developed for improving the prognosis in CRC patients [3]. Advanced CRC is typically treated with monoclonal antibodies targeting epidermal growth factor receptor (EGFR), such as cetuximab or panitumumab, used alone or in combination with standard chemotherapy, but CRC patients harboring KRAS mutations do not respond to the antibodybased anti-EGFR treatment [4].

Methods

Results

Conclusion