Fournier Louis-Alexandre, Kalantari Forouh, Wells James P, Lee Joon Seon, Trigo-Gonzalez Genny, Moksa Michelle M, Smith Theodore, White Justin, Shanks Alynn, Wang Siyun L, Su Edmund, Wang Yemin, Huntsman David G, Hirst Martin, Stirling Peter C
Terry Fox Laboratory, BC Cancer, Vancouver, BC V5L1Z3, Canada.
Interdisciplinary Oncology Program, University of British Columbia, Vancouver, BC V5L1Z3, Canada.
Cancers (Basel). 2024 Aug 24;16(17):2949. doi: 10.3390/cancers16172949.
ARID1A is the core DNA-binding subunit of the BAF chromatin remodeling complex and is mutated in about 8% of all cancers. The frequency of ARID1A loss varies between cancer subtypes, with clear cell ovarian carcinoma (CCOC) presenting the highest incidence at > 50% of cases. Despite a growing understanding of the consequences of ARID1A loss in cancer, there remains limited targeted therapeutic options for ARID1A-deficient cancers. Using a genome-wide CRISPR screening approach, we identify KEAP1 as a genetic dependency of ARID1A in CCOC. Depletion or chemical perturbation of KEAP1 results in selective growth inhibition of ARID1A-KO cell lines and edited primary endometrial epithelial cells. While we confirm that KEAP1-NRF2 signalling is dysregulated in ARID1A-KO cells, we suggest that this synthetic lethality is not due to aberrant NRF2 signalling. Rather, we find that KEAP1 perturbation exacerbates genome instability phenotypes associated with ARID1A deficiency. Together, our findings identify a potentially novel synthetic lethal interaction of ARID1A-deficient cells.
ARID1A是BAF染色质重塑复合体的核心DNA结合亚基，在所有癌症中约有8%发生突变。ARID1A缺失的频率在不同癌症亚型中有所不同，在透明细胞卵巢癌（CCOC）中发生率最高，超过50%的病例存在该情况。尽管人们对ARID1A缺失在癌症中的后果的认识不断加深，但针对ARID1A缺陷型癌症的靶向治疗选择仍然有限。我们采用全基因组CRISPR筛选方法，确定KEAP1是CCOC中ARID1A的遗传依赖性。KEAP1的缺失或化学干扰导致ARID1A基因敲除细胞系和编辑后的原代子宫内膜上皮细胞选择性生长抑制。虽然我们证实ARID1A基因敲除细胞中KEAP1-NRF2信号通路失调，但我们认为这种合成致死性并非由于异常的NRF2信号通路。相反，我们发现KEAP1干扰会加剧与ARID1A缺陷相关的基因组不稳定表型。总之，我们的研究结果确定了ARID1A缺陷细胞中一种潜在的新型合成致死相互作用。
