CRISPR screens identify a novel combination treatment targeting BCL-X-L and WNT signaling for KRAS/BRAF-mutated colorectal cancers
- Authors
- Jung, Hae Rim; Oh, Yumi; Na, Deukchae; Min, Seoyeon; Kang, Jinjoo; Jang, Dongjun; Shin, Seungjae; Kim, Jiwon; Lee, Sang Eun; Jeong, Eui Man; An, Joon Yong; Sung, Chang Ohk; Lee, Won-Suk; Lee, Charles; Cho, Sung-Yup
- Issue Date
- 6-5월-2021
- Publisher
- SPRINGERNATURE
- Citation
- ONCOGENE, v.40, no.18, pp.3287 - 3302
- Indexed
- SCIE
SCOPUS
- Journal Title
- ONCOGENE
- Volume
- 40
- Number
- 18
- Start Page
- 3287
- End Page
- 3302
- URI
- https://scholar.korea.ac.kr/handle/2021.sw.korea/137388
- DOI
- 10.1038/s41388-021-01777-7
- ISSN
- 0950-9232
- Abstract
- Metastatic or recurrent colorectal cancer (CRC) patients require systemic chemotherapy, but the therapeutic options of targeted agents remain limited. CRC patients with KRAS or BRAF gene mutations exhibit a worse prognosis and are resistant to anti-EGFR treatment. Previous studies have shown that the expression of anti-apoptotic protein BCL-X-L is increased in CRC patients with KRAS/BRAF mutations, suggesting BCL-X-L as a therapeutic target for this subgroup. Here, we performed genome-wide CRISPR/Cas9 screens of cell lines with KRAS mutations to investigate the factors required for sensitivity to BCL-X-L inhibitor ABT-263 using single-guide RNAs (sgRNAs) that induce loss-of-function mutations. In the presence of ABT-263, sgRNAs targeting negative regulators of WNT signaling (resulting in WNT activation) were enriched, whereas sgRNAs targeting positive regulators of WNT signaling (resulting in WNT inhibition) were depleted in ABT-263-resistant cells. The activation of WNT signaling was highly associated with an increased expression ratio of anti- to pro-apoptotic BCL-2 family genes in CRC samples. Genetic and pharmacologic inhibition of WNT signaling using beta-catenin short hairpin RNA or TNIK inhibitor NCB-0846, respectively, augmented ABT-263-induced cell death in KRAS/BRAF-mutated cells. Inhibition of WNT signaling resulted in transcriptional repression of the anti-apoptotic BCL-2 family member, MCL1, via the functional inhibition of the beta-catenin-containing complex at the MCL1 promoter. In addition, the combination of ABT-263 and NCB-0846 exhibited synergistic effects in in vivo patient-derived xenograft (PDX) models with KRAS mutations. Our data provide a novel targeted combination treatment strategy for the CRC patient subgroup with KRAS or BRAF mutations.
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Collections - College of Health Sciences > School of Biosystems and Biomedical Sciences > 1. Journal Articles
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