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

  • Oncogene. 2021 May;40(18):3287-3302. doi: 10.1038/s41388-021-01777-7.
Hae Rim Jung   #  1  2 ,  Yumi Oh   #  1  2 ,  Deukchae Na  3 ,  Seoyeon Min  4 ,  Jinjoo Kang  4 ,  Dongjun Jang  5 ,  Seungjae Shin  5 ,  Jiwon Kim  5 ,  Sang Eun Lee  5 ,  Eui Man Jeong  6  7  8  9 ,  Joon Yong An  10 ,  Chang Ohk Sung  11 ,  Won-Suk Lee  12 ,  Charles Lee  4  13 ,  Sung-Yup Cho  14  15  16
Affiliations
  • 1. Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul, Korea.
  • 2. Medical Research Center, Genomic Medicine Institute, Seoul National University College of Medicine, Seoul, Korea.
  • 3. Ewha Institute of Convergence Medicine, Ewha Womans University Mokdong Hospital, Seoul, Korea.
  • 4. Department of Life Science, Ewha Womans University, Seoul, Korea.
  • 5. Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea.
  • 6. Department of Pharmacy, College of Pharmacy, Jeju National University, Jeju Special Self-Governing Province, Korea.
  • 7. Interdisciplinary Graduate Program in Advanced Convergence Technology and Science, Jeju National University, Jeju Special Self-Governing Province, Korea.
  • 8. Bio-Health Materials Core-Facility Center, Jeju National University, Jeju Special Self-Governing Province, Korea.
  • 9. Practical Translational Research Center, Jeju National University, Jeju Special Self-Governing Province, Korea.
  • 10. School of Biosystem and Biomedical Science, College of Health Science, Korea University, Seoul, Korea.
  • 11. Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
  • 12. Department of Surgery, Gil Medical Center, Gachon University, Incheon, Korea.
  • 13. The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA.
  • 14. Medical Research Center, Genomic Medicine Institute, Seoul National University College of Medicine, Seoul, Korea. [email protected].
  • 15. Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea. [email protected].
  • 16. Cancer Research Institute, Seoul National University, Seoul, Korea. [email protected].
  • # Contributed equally.
PMID: 33846570 DOI: 10.1038/s41388-021-01777-7
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.

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