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CRISPR screens identify a novel combination treatment targeting BCL-XL and WNT signaling for KRAS/BRAF-mutated colorectal cancers
- Title
- CRISPR screens identify a novel combination treatment targeting BCL-XL and WNT signaling for KRAS/BRAF-mutated colorectal cancers
- Authors
- Jung H.R.; Oh Y.; Na D.; Min S.; Kang J.; Jang D.; Shin S.; Kim J.; Lee S.E.; Jeong E.M.; An J.Y.; Sung C.O.; Lee W.-S.; Lee C.; Cho S.-Y.
- Ewha Authors
- Charles Lee; 나득채
- SCOPUS Author ID
- Charles Lee; 나득채
- Issue Date
- 2021
- Journal Title
- Oncogene
- ISSN
- 0950-9232
- Citation
- Oncogene vol. 40, no. 18, pp. 3287 - 3302
- Publisher
- Springer Nature
- Indexed
- SCIE; SCOPUS
- Document Type
- Article
- 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-XL is increased in CRC patients with KRAS/BRAF mutations, suggesting BCL-XL 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-XL 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 β-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 β-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. © 2021, The Author(s), under exclusive licence to Springer Nature Limited.
- DOI
- 10.1038/s41388-021-01777-7
- Appears in Collections:
- 자연과학대학 > 생명과학전공 > Journal papers
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