Abstract 2922: RAD51AP1 deficiency enhances the synthetic lethality of the PARP inhibitors in lung cancer
Authors: Jabunnesa Khanom, Nanditi N. Thangaraju, Sonia Batan, Kunal Kumar, Snigdha Ganjikunta, Subash Sundaram, Nikhil Patel, Santhakumar Manicassamy, Puttur D. Prasad, Muthusamy Thnagaraju
Journal: Cancer Research (2025)

Abstract Lung cancer (LC) is the most common cause of cancer-related death in men and women. Currently, the 5-year survival rate for LC is ∼15%. Non-small cell lung cancer (NSCLC) accounts for more than 80% of all LC cases. About two-thirds of all patients with newly diagnosed NSCLC have advanced disease (stage III or IV), and they can be managed using palliative chemotherapy if they cannot benefit from the targeted therapy. The standard primary treatment for these patients is a combination of platinum-based chemotherapeutic agents. However, the critical barrier to using platinum-based chemotherapy is that it has high toxicity, especially nephrotoxicity and myelosuppression, and acquired drug resistance. Therefore, the development of a new and effective therapeutic strategy is a major unmet medical need and should have a high clinical impact on the treatment of NSCLC. Recently, poly (ADP-ribose) polymerase (PARP) inhibitors, Olaparib (AZD2281) and Talazoparib (BMN 673) offer an attractive new therapeutic avenue for the treatment of NSCLC as they are largely less toxic than platinum-based drugs. Although PARP inhibitor treatment alone has a significant impact on the overall survival of NSCLC patients, PARP inhibitors should have more clinical benefit in patients with a deficiency in homologous recombination (HR). RAD51AP1, HR protein involved in DNA repair and chemotherapy resistance. Therefore, the RAD51AP1 deficiency should potentiate the anticancer potential of PARP inhibitors and have a high clinical impact on the treatment of NSCLC, including KRAS-mutant NSCLC patients. We found that RAD51AP1 knockdown significantly enhances PARP inhibitor response in both KRAS-wildtype NSCLC cell lines (H1299 and HCC827) and KRAS-mutant NSCLC cell lines (H1734 and H358). However, RAD51AP1 knockdown did not affect the normal lung epithelial cells (HEL299 and HSAEC). Rad51ap1 knockout mice are resilient in the KRAS mutation-induced spontaneous mouse lung cancer (Rad51ap1-/--KrasLA2) and significantly enhanced PARP inhibitors, Olaparib and Talazoparib, response. However, PARP inhibitor treatment does not have a significant response in Rad51ap1-/--KrasLA2. RNA-seq analysis provides evidence that Rad51ap1 deficiency enhances chemotherapy response by limiting signaling pathways that are associated with drug resistance and efflux. Overall, our results provide a mechanism-based novel therapeutic strategy for the treatment of NSCLC and the identification of RAD51AP1 inhibitor should have a significant clinical impact on the prevention and treatment of NSCLC Citation Format: Jabunnesa Khanom, Nanditi N. Thangaraju, Sonia Batan, Kunal Kumar, Snigdha Ganjikunta, Subash Sundaram, Nikhil Patel, Santhakumar Manicassamy, Puttur D. Prasad, Muthusamy Thnagaraju. RAD51AP1 deficiency enhances the synthetic lethality of the PARP inhibitors in lung cancer [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 2922.