CRISPR screens identify a novel combination treatment targeting BCL-X-L and WNT signaling for KRAS/BRAF-mutated colorectal cancers
DC Field | Value | Language |
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dc.contributor.author | Jung, Hae Rim | - |
dc.contributor.author | Oh, Yumi | - |
dc.contributor.author | Na, Deukchae | - |
dc.contributor.author | Min, Seoyeon | - |
dc.contributor.author | Kang, Jinjoo | - |
dc.contributor.author | Jang, Dongjun | - |
dc.contributor.author | Shin, Seungjae | - |
dc.contributor.author | Kim, Jiwon | - |
dc.contributor.author | Lee, Sang Eun | - |
dc.contributor.author | Jeong, Eui Man | - |
dc.contributor.author | An, Joon Yong | - |
dc.contributor.author | Sung, Chang Ohk | - |
dc.contributor.author | Lee, Won-Suk | - |
dc.contributor.author | Lee, Charles | - |
dc.contributor.author | Cho, Sung-Yup | - |
dc.date.accessioned | 2021-05-24T06:40:04Z | - |
dc.date.available | 2021-05-24T06:40:04Z | - |
dc.date.created | 2021-04-22 | - |
dc.date.issued | 2021-05-06 | - |
dc.identifier.issn | 0950-9232 | - |
dc.identifier.uri | https://scholarworks.bwise.kr/gachon/handle/2020.sw.gachon/81080 | - |
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 | 영어 | - |
dc.language.iso | en | - |
dc.publisher | SPRINGERNATURE | - |
dc.relation.isPartOf | ONCOGENE | - |
dc.title | CRISPR screens identify a novel combination treatment targeting BCL-X-L and WNT signaling for KRAS/BRAF-mutated colorectal cancers | - |
dc.type | Article | - |
dc.type.rims | ART | - |
dc.description.journalClass | 1 | - |
dc.identifier.wosid | 000639635100005 | - |
dc.identifier.doi | 10.1038/s41388-021-01777-7 | - |
dc.identifier.bibliographicCitation | ONCOGENE, v.40, no.18, pp.3287 - 3302 | - |
dc.description.isOpenAccess | N | - |
dc.identifier.scopusid | 2-s2.0-85104106253 | - |
dc.citation.endPage | 3302 | - |
dc.citation.startPage | 3287 | - |
dc.citation.title | ONCOGENE | - |
dc.citation.volume | 40 | - |
dc.citation.number | 18 | - |
dc.contributor.affiliatedAuthor | Lee, Won-Suk | - |
dc.type.docType | Article in Press | - |
dc.description.journalRegisteredClass | scie | - |
dc.description.journalRegisteredClass | scopus | - |
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