KLI

CRISPR screens identify a novel combination treatment targeting BCL-X-L and WNT signaling for KRAS/BRAF-mutated colorectal cancers

Metadata Downloads
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.
Author(s)
강진주김지원나덕채민서연성창옥신승재안준용오유미이상은이원석장동준정의만정해림조성엽Charles Lee
Issued Date
2021
Type
Article
Keyword
Colorectal Neopla는humansProto-Oncogene Proteins B-rafProto-Oncogene Proteins p21(ras)쭛 signaling Pathway
DOI
10.1038/s41388-021-01777-7
URI
https://oak.ulsan.ac.kr/handle/2021.oak/7468
https://ulsan-primo.hosted.exlibrisgroup.com/primo-explore/fulldisplay?docid=TN_cdi_pubmed_primary_33846570&context=PC&vid=ULSAN&lang=ko_KR&search_scope=default_scope&adaptor=primo_central_multiple_fe&tab=default_tab&query=any,contains,CRISPR%20screens%20identify%20a%20novel%20combination%20treatment%20targeting%20BCL-X-L%20and%20WNT%20signaling%20for%20KRAS%2FBRAF-mutated%20colorectal%20cancers&offset=0&pcAvailability=true
Publisher
ONCOGENE
Location
영국
Language
영어
ISSN
0950-9232
Citation Volume
40
Citation Number
18
Citation Start Page
3287
Citation End Page
3302
Appears in Collections:
Medicine > Medicine
Authorize & License
  • Authorize공개
Files in This Item:
  • There are no files associated with this item.

Items in Repository are protected by copyright, with all rights reserved, unless otherwise indicated.