The Expansion of Drug Tolerant Persister Models

Chemotherapy resistance is a significant challenge in colorectal cancer (CRC) therapy. Recent studies have identified drug-tolerant persister cells (DTPs) as key contributors to non-genetic resistance. DTPs are a subpopulation of cancer cells that are slow-cycling or non-proliferative, evading treatment and resuming growth once treatment pressure is lifted. This project develops additional DTP models, including (1) a syngeneic and (2) a breast cancer model. In vivo trials with murine CRC cell lines (CT26, MC38) yielded promising results. While irinotecan (CPT-11) alone did not induce tumour regression, combination therapies with 5FU/LV, oxaliplatin (OX), and cyclophosphamide (CP) were effective but toxic —the addition of anti-PD1 produced variable regrowth. Most treated CT26 tumours were no longer palpably detectable, while all MC38 tumours maintained this state, with no regrowth observed. The final regimen of 5-FU/LV, OX, and CPT-11 stabilized growth but did not achieve regression, with growth was observed roughly three weeks on treatment. In vitro studies revealed that colorectal cancer (CT26, MC38) and breast cancer (MDA-MB-231, BT474) cell lines survive treatment by entering a drug-tolerant state, characterized by key DTP hallmarks such as regrowth, maintained sensitivity to re-treatment, slow cycling, and hypo-transcription.