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To elucidate the epigenetic mechanisms of drug resistance, epigenetically reprogrammed H460 cancer cells (R-H460) were established by the transient introduction of reprogramming factors. Then, the R-H460 cells were induced to differentiate by the withdrawal of stem cell media for various durations, which resulted in differentiated R-H460 cells (dR-H460). Notably, dR-H460 cells differentiated for 13 days (13dR-H460 cells) formed a significantly greater number of colonies showing drug resistance to both cisplatin and paclitaxel, whereas the dR-H460 cells differentiated for 40 days (40dR-H460 cells) lost drug resistance; this suggests that 13dR-cancer cells present short-term resistance (less than a month). Similarly, increased drug resistance to both cisplatin and paclitaxel was observed in another R-cancer cell model prepared from N87 cells. The resistant phenotype of the cisplatin-resistant (CR) colonies obtained through cisplatin treatment was maintained for 2–3 months after drug treatment, suggesting that drug treatment transforms cells with short-term resistance into cells with medium-term resistance. In single-cell analyses, heterogeneity was not found to increase in 13dR-H460 cells, suggesting that cancer cells with short-term resistance, rather than heterogeneous cells, may confer epigenetically driven drug resistance in our reprogrammed cancer model. The epigenetically driven short-term and medium-term drug resistance mechanisms could provide new cancer-fighting strategies involving the control of cancer cells during epigenetic transition., Cancer chemotherapy: treatment prolongs resistance caused by DNA modification Cancer cells that are transiently resistant to drug therapies owing to changes in their gene expression patterns can become resistant for longer durations if exposed to the drug treatments. A team led by Kyeong-Man Hong and Hyonchol Jang from the National Cancer Center in Goyang, South Korea, used cellular reprogramming technologies to induce changes in the DNA markers that regulate gene expression. Working with lung and gastric cancer cell lines, the researchers found that such epigenetic alterations caused many cells to become resistant to the chemotherapy drugs cisplatin and paclitaxel. In the absence of treatment, the cells soon lost their drug resistance. In the presence of the chemotherapeutics, however, the resistance trait lasted longer, a finding that could inform best practice for how to administer cancer-fighting agents in the face of epigenetic-driven drug resistance.