Full metadata record
DC Field | Value | Language |
---|---|---|
dc.contributor.author | Charles Lee | * |
dc.contributor.author | 나득채 | * |
dc.date.accessioned | 2021-06-07T16:31:30Z | - |
dc.date.available | 2021-06-07T16:31:30Z | - |
dc.date.issued | 2021 | * |
dc.identifier.issn | 0950-9232 | * |
dc.identifier.other | OAK-29357 | * |
dc.identifier.uri | https://dspace.ewha.ac.kr/handle/2015.oak/257633 | - |
dc.description.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. | * |
dc.language | English | * |
dc.publisher | Springer Nature | * |
dc.title | CRISPR screens identify a novel combination treatment targeting BCL-XL and WNT signaling for KRAS/BRAF-mutated colorectal cancers | * |
dc.type | Article | * |
dc.relation.issue | 18 | * |
dc.relation.volume | 40 | * |
dc.relation.index | SCIE | * |
dc.relation.index | SCOPUS | * |
dc.relation.startpage | 3287 | * |
dc.relation.lastpage | 3302 | * |
dc.relation.journaltitle | Oncogene | * |
dc.identifier.doi | 10.1038/s41388-021-01777-7 | * |
dc.identifier.wosid | WOS:000639635100005 | * |
dc.identifier.scopusid | 2-s2.0-85104106253 | * |
dc.author.google | Jung H.R. | * |
dc.author.google | Oh Y. | * |
dc.author.google | Na D. | * |
dc.author.google | Min S. | * |
dc.author.google | Kang J. | * |
dc.author.google | Jang D. | * |
dc.author.google | Shin S. | * |
dc.author.google | Kim J. | * |
dc.author.google | Lee S.E. | * |
dc.author.google | Jeong E.M. | * |
dc.author.google | An J.Y. | * |
dc.author.google | Sung C.O. | * |
dc.author.google | Lee W.-S. | * |
dc.author.google | Lee C. | * |
dc.author.google | Cho S.-Y. | * |
dc.contributor.scopusid | Charles Lee(23980489900;57290864600) | * |
dc.contributor.scopusid | 나득채(37034738100) | * |
dc.date.modifydate | 20240318140645 | * |