Folate receptor α increases chemotherapy resistance through stabilizing MDM2 in cooperation with PHB2 that is overcome by MORAb‐202 in gastric cancer

Abstract Background The main function of folate receptor α (FOLRα) has been considered to mediate intracellular folate uptake and induce tumor cell proliferation. Given the broad spectrum of expression among malignant tumors, including gastric cancer (GC) but not in normal tissue, FOLRα represents an attractive target for tumor‐selective drug delivery. However, the efficacy of anti‐FOLRα monoclonal antibodies (mAbs) has not been proved so far, with the reason for this failure remaining unclear, raising the need for a better understanding of FOLRα function. Methods The distribution of FOLRα in GC cells was evaluated by immunohistochemistry. The impacts of FOLRα expression on the survival of GC patients and GC cell lines were examined with the Gene Expression Omnibus database and by siRNA of FOLRα. RNA‐sequencing and Microarray analysis was conducted to identify the function of FOLRα. Proteins that interact with FOLRα were identified with shotgun LC‐MS/MS. The antitumor efficacy of the anti‐FOLRα mAb farletuzumab as well as the antibody‐drug conjugate (ADC) consists of the farletuzumab and the tublin‐depolymerizing agent eribulin (MORAb‐202) was evaluated both in vitro and in vivo. Results FOLRα was detected both at the cell membrane and in the cytoplasm. Shorter overall survival was associated with FOLRα expression in GC patients, whereas reduction of FOLRα attenuated cell proliferation without inducing cell death in GC cell lines. Transcriptomic and proteomic examinations revealed that the FOLRα‐expressing cancer cells possess a mechanism of chemotherapy resistance supported by MDM2, and FOLRα indirectly regulates it through a chaperone protein prohibitin2 (PHB2). Although reduction of FOLRα brought about vulnerability for oxaliplatin by diminishing MDM2 expression, farletuzumab did not suppress the MDM2‐mediated chemoresistance and cell proliferation in GC cells. On the other hand, MORAb‐202 showed significant antitumor efficacy. Conclusions The ADC could be a more reasonable choice than mAb as a targeting agent for the FOLRα‐expressing tumor