Abstract P077: SCO-101 mediates re-sensitization of irinotecan (SN38) resistant colorectal cancer cells

Abstract

Abstract Introduction: Annually, more than 500.000 die from Colorectal Cancer (CRC). Three types of chemotherapy are currently being used worldwide to treat CRC patients: 5FU, oxaliplatin and irinotecan. Unfortunately, chemotherapy resistance is present or develops in the majority of metastatic CRC patients. Resistance to anti-cancer drugs represents the main cause of cancer-related deaths. Thus, re-sensitization of chemotherapy resistant cancer cells constitutes a highly unmet medical need. The small molecule drug, SCO-101, is an oral drug and has passed 4 Phase I clinical trials where it demonstrated excellent PK and favourable safety profile. Materials and Methods: We used pairs of parental (sensitive) and SN38-resistant (SN38 is the active metabolite of irinotecan) human colon cancer cell lines (HT29 and LoVo). Inhibition of ABCG2 was known re-sensitize the SN38 resistant cells and SCO-101 was investigated for effects on ABCG2 by dye-flux assays, bi-directinal fluz assays and vesicular uptake assays. The impact on the levels of ABCG2 was investigated in the presence or absence of SCO-101. Furthermore, a kinase screen revealed that the kinase SRPK1 was inhibited by SCO-101 and the importance of SRPK1 activity in re-sensitization of SN38 resistant colon cancer cells was investigated by two different synthetic SRPK1 inhbitors. The effect of SCO-101 was investigated by cell viability assays (MTT/PresoBlue) in vitro during 72h exposure to SCO-101 and/or SN38. Results: Updated results from the various flux assays clearly demonstrated that SCO-101 inhibited the activity of ABCG2 (BCRP). Protein analysis further demonstrated that SCO-101 causes degradation of ABCG2/BCRP and in silco docking predicted SCO-101 to bind in the part of ABCG2 whwere also SN38 binds. Cell viability assays with two different SRPK1 inhibitors demonstrated that this kinase is involved in re-sensitization to SN38. Exposing SN38-resistant cells to the combination of SCO-101 and SN38, had a significant inhibitory effect on cell viability compared to either drug alone, suggesting an additive or synergistic effect between these two drugs with SCO-101 re-sensitizing the resistant cells to SN38. Conclusion and future perspectives: These preclinical studies demonstrate that SCO-101 sensitizes SN38-resistant colon cancer cells to SN38 through inhibition of the SRPK1 kinase and inhibition/degradation of the ABCG2/BCRP drug efflux pump. In conclusion, SCO-101 represents a unique drug with an innovative dual mechanism of action. Scandion Oncology has reported the outcome of the first part of the ongoing Phase II clinical CORIST trial with metastatic CRC patients, who have developed acquired resistance to irinotecan containing treatment. These patients were be re-exposed to the combination of irinotecan containing treatment and SCO-101 (www.clinicaltrials.gov/ct2/show/NCT04247256?term=scandion&draw=2&rank=2). Citation Format: Jan Stenvang, Nicklas Lindland Roest, Peter Michael Vestlev, Bo Rode Hansen. SCO-101 mediates re-sensitization of irinotecan (SN38) resistant colorectal cancer cells [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P077.