Targeting REV1 Exposes Context-Dependent Therapeutic Responses in Colorectal Cancer

Targeting REV1 reveals context-dependent therapeutic responses in colorectal cancer. The enzyme REV1, crucial for translesion synthesis, may be a promising target to boost the effectiveness of chemotherapy. In this study, pharmacologic and genetic REV1 inhibition in colorectal cancer cells and patient-derived organoids showed varying sensitization to chemotherapeutic agents, depending on the treatment and cellular context.

For instance, the REV1 inhibitor JH-RE-06 increased sensitivity to oxaliplatin in HCT116 cells and 5-fluorouracil in HT-29 cells, but combinations of drugs often showed minimal additional benefit. Similarly, siRNA depletion of REV1 similarly enhanced chemotherapy sensitivity, supporting its role in these effects. However, NO nitro compound sensitivity tests and MLH1 expression analyses did not reveal consistent changes in mismatch repair function.

Genetic sequencing did not detect any alterations in the region examined. Chemosensitization was not linked to consistent increases in caspase-3/7 activation. REV1 inhibition also triggered autophagy-related LC3-II accumulation and reduced beta-tubulin levels after prolonged exposure. In two patient-derived CRC organoid models, JH-RE-06 demonstrated single-agent growth inhibition, with half-maximal inhibitory concentrations of 2.01 micromolar and 1.4 micromolar, respectively.

These findings highlight the context-dependent outcomes of REV1 targeting, suggesting potential therapeutic implications beyond the known TLS-mediated DNA damage tolerance.