Abstract 5726: QLS1103, A highly potent and selective PARP7 inhibitor treating advanced solid tumors

PARP7, a member of the ADP-ribose polymerase family, is an enzyme that modifies proteins by attaching mono ADP-ribose to substrates. This post-translational modification is crucial for a variety of cellular functions, including the regulation of innate immune responses, the control of autophagy, and the facilitation of apoptosis. In some tumor cells, PARP7 may facilitate immune surveillance evasion by inhibiting type I interferon signaling pathways. Additionally, PARP7 has been reported to promote tumor growth in a cell-autonomous manner. Due to its multifaceted functions, PARP7 is an important target for cancer research and therapeutic intervention. QLS1103 is a proprietary, highly potent and selective PARP7 inhibitor. Study findings showed that treatment with QLS1103 may restore Type I IFN responses in tumor cells and trigger anti-tumor immunity in CT26 and EO771 syngeneic models. Analysis of tumor-infiltrating lymphocytes (TILs) revealed that QLS1103 not only increases the percentage of TILs but also enhances the activity of cytotoxic T cells. Furthermore, the combination of QLS1103 with an anti-PD-1 antibody showed a significant survival benefit over monotherapy in the CT26 model, with a complete regression (CR) rate rising to 75% in the combination group, compared to 25% in the monotherapy group. QLS1103 was also evaluated in a lung cancer xenograft model (NCI-H1373) to confirm the cell-autonomous effects of PARP7 inhibition. It was observed that QLS1103 could dose-dependently inhibit tumor growth and even induce tumor regression. QLS1103 has exhibited a favorable safety profile with excellent safety margins in preclinical studies and is currently under investigation in a phase I clinical trial. In conclusion, QLS1103 emerges as a promising candidate for the treatment of advanced solid tumors, either as a monotherapy or in combination with immune checkpoint inhibitors, warranting further investigation in clinical settings to fully realize its therapeutic potential. Citation Format: Yuxing Zhang, Xiaoxia Yan, Yiming Xu, Difei Dong, Huijie Guo, Junguo Hao, Xinrui Shao, Ling Li, Guanxin Huang, Dong Yang, Guqin Shi, Yanling Xu, Daqing Sun, Weimei Sun, Weikang Tao. QLS1103, A highly potent and selective PARP7 inhibitor treating advanced solid tumors [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 5726.