Transcriptomic analyses of PDX tumors (QQX-17) to gain insight into the mechanisms underlying FOLFOXIRI-induced DTP state.

Chemotherapy resistance remains a significant challenge, often leading to tumor relapse and poor prognosis. While past efforts to overcome treatment resistance have focused primarily on genetic alterations—such as somatic mutations, chromosomal aberrations, and dysregulated signaling pathways—these insights have yet to translate into effective clinical interventions. The recent discovery of drug-tolerant persister (DTP) cells, which survive therapy through reversible, non-genetic adaptations akin to embryonic diapause, has unveiled a novel mechanism of chemotherapy resistance. To investigate this further, we employed treatment-naïve colorectal cancer (CRC) patient-derived xenograft (PDX) models. Upon reaching a tumor volume of 100 mm³, the PDX models were treated with a single maximum-tolerated dose of the FOLFOXIRI regimen. Post-treatment responses varied, including initial tumor shrinkage followed by regrowth, mirroring the "sensitivity-DTP-regrowth" pattern observed in CRC patients. Transcriptomic analyses of these PDX tumors were then conducted to elucidate the mechanisms underlying the FOLFOXIRI-induced DTP state.