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

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

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. csybio@snu.ac.kr.
  • 15 Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea. csybio@snu.ac.kr.
  • 16 Cancer Research Institute, Seoul National University, Seoul, Korea. csybio@snu.ac.kr.
  • # 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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