Chemotherapy is the backbone of subsequent treatment for patients with
lung adenocarcinoma (LUAD) exhibiting radiation resistance, and
pemetrexed plays a critical role in this
chemotherapy. However, few studies have assessed changes in the sensitivity of LUAD cells to
pemetrexed under radioresistant circumstances. Therefore, the objectives of this study were to delineate changes in the sensitivity of radioresistant LUAD cells to
pemetrexed and to elucidate the related mechanisms and then develop an optimal strategy to improve the cytotoxicity of
pemetrexed in radioresistant LUAD cells. Our study showed a much lower efficacy of
pemetrexed in radioresistant cells than in parental cells, and the mechanism of action was the significant downregulation of
folate receptor alpha (FRα) by long-term fractionated
radiotherapy, which resulted in less cellular
pemetrexed accumulation. Interestingly,
decitabine effectively reversed the decrease in FRα expression in radioresistant cells through an indirect regulatory approach. Thereafter, we designed a combination
therapy of
pemetrexed and
decitabine and showed that the activation of FRα by
decitabine sensitizes radioresistant LUAD cells to
pemetrexed both in vitro and in xenografts. Our findings raised a question regarding the administration of
pemetrexed to patients with LUAD exhibiting acquired radioresistance and accordingly suggested that a combination of
pemetrexed and
decitabine would be a promising treatment strategy.