Abstract P86: A drug repurposing screen identified efficacious topoisomerase II (TOP2) inhibitors against mutant KRAS-driven colon cancer metastasis
Yilong Zheng, Anya Ramanan, Andrea York Tiang Teo, Dominic Wei Ting Yap, Yang Lv, Gracie Wee Ling Eng, Jit Kong CheongAbstract
Background:
Colorectal cancer (CRC) is the third most common malignancy worldwide. Mortality is largely due to limited treatment options for patients who present with advanced disease. Oncogenic mutations in KRAS occur in approximately 30-50% of CRC, driving tumor progression and influencing efficacy of both cytotoxic and targeted therapies. KRAS-mutant CRCs, in particular, progress rapidly into metastatic disease and are associated with a higher cumulative incidence of metastases to lung, bone, and brain, which results in poorer prognosis.
Methods:
We established a mutant KRAS-driven in vitro three-dimensional (3D) colon tumoroid system and used it to perform a FDA-approved drug repurposing screen with the aim of identifying compounds that are efficacious against mutant KRAS-driven colon cancer metastasis.
Results:
We demonstrate that CRISPR-mediated knockout of the mutant KRAS (G13D) allele in our in vitro 3D HCT116 colon tumoroids induced upregulation of cell adhesion molecules and dramatically reduced the abundance of non-tumoroid forming cells. Using the parental HCT116 colon tumoroids, we conducted a high throughput phenotypic screen with a unique collection of 978 FDA-approved drugs to identify compounds that specifically eliminates non-tumoroid forming HCT116 colon cancer cells. We demonstrate that topoisomerase II (TOP2) inhibitors are enriched in our drug screen and validated their anti-cell migration and invasion properties using orthogonal approaches, such as wound healing and extracellular matrix (ECM) transwell assays.
Conclusion:
Although TOP2 inhibitors have been shown to be efficacious against primary colorectal cancer and other solid tumors, their impact and mechanism-of-action on mCRC remains largely unknown. Our ongoing studies seek to elucidate their mechanism-of-action(s) on mutant KRAS-driven colon cancer cell migration and invasion.
Citation Format:
Yilong Zheng, Anya Ramanan, Andrea York Tiang Teo, Dominic Wei Ting Yap, Yang Lv, Gracie Wee Ling Eng, Jit Kong Cheong. A drug repurposing screen identified efficacious topoisomerase II (TOP2) inhibitors against mutant KRAS-driven colon cancer metastasis [abstract]. In: Proceedings of Frontiers in Cancer Science 2025; 2025 Nov 5-7; Singapore. Philadelphia (PA): AACR; Cancer Res 2026;86(13_Suppl):Abstract nr P86.