Abstract
Although oxaliplatin-based chemotherapy is the current standard adjuvant therapy for colorectal cancer (CRC), the molecular mechanisms underlying oxaliplatin resistance remain unclear. Here, we examined the molecular mechanisms underlying SLC22A18-associated oxaliplatin resistance and strategies for overcoming oxaliplatin resistance. We evaluated the association between SLC22A18 and prognosis in 337 patients with CRC and its functional significance and studied the mechanisms through which SLC22A18 affects oxaliplatin resistance development in CRC cells, using CRC cell lines and patient-derived cells (PDCs). SLC22A18 downregulation was positively correlated with worse survival in patients with CRC. Low SLC22A18-expressing cells showed relatively lower sensitivity to oxaliplatin than high SLC22A18-expressing cells. In addition, ERK activation was found to be involved in the mechanisms underlying SLC22A18-related oxaliplatin resistance. To confirm ERK pathway dependence, we used an ERK inhibitor and found that combined treatment with oxaliplatin and the ERK inhibitor overcame oxaliplatin resistance in the low SLC22A18-expressing cells. Ex vivo approaches using PDC confirmed the correlation between SLC22A18 expression and oxaliplatin resistance. Results of the in vivo study showed that SLC22A18 expression regulated oxaliplatin efficacy, and that combined treatment with an ERK inhibitor could be a useful therapeutic strategy when SLC22A18 is downregulated. Together, our findings indicate that SLC22A18 could serve as a biomarker for the prediction of oxaliplatin resistance. In cases of oxaliplatin resistance due to low SLC22A18 expression, resistance can be overcome by combined treatment with an ERK inhibitor.