Targeting Drug Tolerant Persisters (DTPs) in Colorectal Cancer via Anti-apoptosis Inhibition

Chemotherapy resistance presents a major challenge to successful therapy in colorectal cancer (CRC). Non-genetic processes can drive drug resistance, and drug tolerant persister (DTP) cells are emerging as key players. DTPs are slow-cycling cancer cells and represent a reversible state, where upon removal of treatment they resume growth yet remain sensitive to therapy. We demonstrate that patient-derived CRC tumours exposed to chemotherapy (CPT-11) and cell cultures exposed to its active metabolite (SN38) survive by entering the DTP state. This project reveals increased expression of autophagy(definition) and anti-apoptotic genes, and increased expression of the anti-apoptotic protein Bcl-xL, in SN38-induced DTPs. Annexin V/PI analysis reveals SN38 treatment in combination with an anti-apoptotic (ABT-263) and autophagy (SBI) inhibitor significantly increases cell death. Furthermore, only cultures treated with SN38, ABT-263, and SBI in combination failed to regrow following a 28-day drug holiday, suggesting the autophagy and anti-apoptotic pathways work together to promote DTP survival.