Abstract 4189: CRISPR-edited cell lines targeting key molecular pathways: Accelerating the development of synthetic lethal therapeutics beyond PARP inhibitors

Abstract Synthetic lethality (SL) has emerged as a highly promising therapeutic strategy, gaining significant attention in the field of cancer treatment in recent years. The principle behind SL is that the simultaneous loss or inhibition of two genes results in cell death, while the inhibition of only one gene does not. SL drugs exploit this mechanism by targeting the partner gene of an already inactivated or mutated gene in cancer cells, inducing their death. This approach allows for the precise targeting of genetic vulnerabilities specific to cancer cells, sparing normal tissues from damage. Additionally, SL therapies expand the range of druggable targets, including proteins that are difficult to inhibit with traditional small molecules. By affecting both enzymatic and non-enzymatic protein functions, SL therapies reduce the risk of developing drug resistance, providing an effective option for treating cancers that are resistant to conventional therapies.Kyinno offers an extensive collection of knockout cell lines targeting a range of genes associated with synthetic lethality, including SHLD2, P53, T53BP1, AQR, ATRX, SETD2, ATM, WRN, BRCA1, and BRCA2. These cell lines, developed using the CRISPR/Cas9 genome editing technique and validated through sequencing and western blot analysis, are crucial for investigating the complex mechanisms underlying synthetic lethality and for identifying novel therapeutic strategies in cancer treatment. For example, our knockout lines for BRCA1 and BRCA2 enable researchers to investigate vulnerabilities in homologous recombination repair, paving the way for the development of innovative PARP inhibitors and targeted therapies. Additionally, lines with deletions in ATM and WRN provide essential insights into DNA damage response pathways, which can enhance the effectiveness of DNA-damaging agents. The diverse range of gene knockouts, including those involved in cell cycle regulation, DNA repair, and apoptosis, allows for comprehensive studies into the synergistic effects of dual gene inhibition. By utilizing our extensive library of synthetic lethality cell lines, researchers can effectively validate hypotheses, screen novel drug candidates, and optimize combination therapies to improve outcomes for patients with resistant cancers. We highly recommend these resources for advancing research in synthetic lethality and targeted cancer therapies. Citation Format: Yue Huang, Yunpeng Zhai, Yan Feng, Xinyue Jia, Xiaohuan Zhang, Jinying Ning, Feng Hao. CRISPR-edited cell lines targeting key molecular pathways: Accelerating the development of synthetic lethal therapeutics beyond PARP inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4189.