Abstract The approval of sotorasib and adagrasib as the first KRAS G12C inhibitors has made RAS oncogene a druggable target. However, they have limited overall objective response rates and short response durations. Therefore, strategies for improving RAS-targeted cancer therapy are urgently needed. To this end, we found that both sotorasib and adagrasib promoted topoisomerase IIa (Topo IIa) proteasomal degradation in KRAS G12C mutant cancer cells and induced DNA damage and apoptosis. In cell lines with sotorasib acquired resistance, elevated Topo IIa levels were detected. TOP2A overexpression in sensitive KRAS G12C mutant cells conferred resistance to sotorasib, whereas TOP2A knockdown in sotorasib-resistant cell lines sensitized the cells to sotorasib. Moreover, the combination of a KRAS G12C inhibitor such as sotorasib with a Topo II inhibitor such as VP-16, synergistically decreased the survival of sotorasib-resistant RAS G12C mutant cells with augmented induction of DNA damage and apoptosis, effectively inhibited the growth of sotorasib-resistant tumors, and delayed or prevented the emergence of sotorasib acquired resistance in vivo. Collectively, our results reveal an essential role of Topo IIa inhibition in mediating the therapeutic efficacy of Ras-targeted cancer therapy, providing a strong scientific rationale for targeting Topo II to improve the efficacy of RAS-targeted cancer therapy. Citation Format: Rongzhong Xu, Dongsheng Wang, Guangzhi Ma, Xun Yuan, Qian Chu, Rener Zhang, Pan Du, Shidong Jia, Ticiana Leal, Suresh S Ramalingam, Zhen Chen, Shi-Yong Sun. Enhancing therapeutic efficacy of RAS-targeted cancer therapy via co-targeting DNA topoisomerase II abstract. In: Proceedings of the AACR Special Conference in Cancer Research: RAS Oncogenesis and Therapeutics; 2026 Mar 5-8; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Res 2026;86 (5Suppl₁): Abstract nr A021.
Xu et al. (Thu,) studied this question.