Identification of BIK as an unfavorable prognostic marker and novel therapeutic target in microsatellite stable colorectal cancer harboring KRAS mutations

Peng Liu; Feng Jiao; Zhenghua Zhang; Feilong Zhao; Jinping Cai; Shiqing Chen; Tao Fu; Min Li

Identification of BIK as an unfavorable prognostic marker and novel therapeutic target in microsatellite stable colorectal cancer harboring KRAS mutations

Am J Cancer Res. 2022 Nov 15;12(11):5300-5314. eCollection 2022.

Authors

Peng Liu¹, Feng Jiao², Zhenghua Zhang³, Feilong Zhao⁴, Jinping Cai⁴, Shiqing Chen⁴, Tao Fu⁵, Min Li⁶

Affiliations

¹ Department of Colorectal Surgery, Changhai Hospital, Naval Medical University Shanghai, China.
² Department of Oncology, Renji Hospital, School of Medicine, Shanghai Jiaotong University Shanghai, China.
³ Department of Oncology, Jing'an District Centre Hospital of Shanghai, Huashan Hospital Fudan University Jing'an Branch Shanghai, China.
⁴ Medical Affairs, 3D Medicines, Inc. Shanghai, China.
⁵ Department of Gastrointestinal Surgery, China-Japan Friendship Hospital Beijing, China.
⁶ Department of Oncology, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine Nanjing, Jiangsu, China.

PMID: 36504908
PMCID: PMC9729897

Abstract

KRAS mutations lead to persistent activation of multiple downstream effectors that drive the cancer phenotype. Approximately 30%-50% of colorectal cancer (CRC) patients harbor KRAS mutations, which confer more aggressive tumor biology and shorter overall survival (OS), especially in microsatellite stable (MSS) metastatic CRC. Given that KRAS mutant protein has been proven difficult to target directly, identifying genes that function closely with KRAS and targeting these genes seems to be a promising therapeutic strategy for KRAS-mutated MSS CRC. Here, KRAS function-sensitive genes were identified by assessing the correlation between gene dependency scores from CRISPR knockout screens and KRAS mRNA expression in KRAS-mutated MSS CRC cell lines in the Cancer Cell Line Encyclopedia (CCLE) database. If the correlation coefficient was ≥ 0.6, the gene was considered a KRAS function-sensitive gene. Then KRAS function-sensitive genes related to prognosis were screened out in The Cancer Genome Atlas (TCGA) cohort, and the prognostic value was validated in the Gene Expression Omnibus (GEO) cohort. Single-sample gene set enrichment analysis (ssGSEA) was performed to investigate the potential mechanisms. PockDrug-Server was used to predict the druggability of candidate genes. The results showed that in 20 KRAS-mutated MSS CRC cell lines, 13 genes were identified as KRAS function-sensitive genes. Of these 13 genes, only BIK expression was significantly associated with progression-free survival (PFS) and OS, and the BIK-high patients had significantly poorer PFS (HR=3.18, P=0.020) and OS (HR=4.74, P=0.030) than the BIK-low patients. Multivariate Cox regression analysis revealed high BIK expression as an independent predictor for poorer prognosis in KRAS-mutated MSS CRC. The prognostic value of BIK was also successfully validated in a GEO cohort. The results of ssGSEA showed that the BIK-high group was more prone to strong metastasis activity than the BIK-low group. Pocket druggability prediction analysis presented that BIK had three druggable pockets, and their druggability scores were above 0.8. These findings suggested that BIK is a promising prognostic marker and therapeutic target in KRAS-mutated MSS CRC.

Keywords: BIK; Colorectal cancer; KRAS function-sensitive genes; KRAS mutations; microsatellite stable.