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.
Original language | English |
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Pages (from-to) | 3287-3302 |
Number of pages | 16 |
Journal | Oncogene |
Volume | 40 |
Issue number | 18 |
DOIs | |
Publication status | Published - 2021 May 6 |
Bibliographical note
Funding Information:Acknowledgements This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIP) (grant No. 2017R1C1B2002183); the Bio & Medical Technology Development Program of the NRF funded by the Ministry of Science & ICT (grant No. 2018M3A9F3056902 and 2019M3E5D4066900); Creative-Pioneering Researchers Program through Seoul National University (grant No. 800-20200510); and the Collaborative Research Program of SNU Boramae Medical Center and Basic Medical Science from Seoul National University College of Medicine (grant No. 800-20200005).
Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature Limited.
ASJC Scopus subject areas
- Molecular Biology
- Genetics
- Cancer Research