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

The main function of folate receptor ? (FOLR?) 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, FOLR? represents an attractive target for tumor-selective drug delivery. However, the ...
efficacy of anti-FOLR? 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 FOLR? function.The distribution of FOLR? in GC cells was evaluated by immunohistochemistry. The impacts of FOLR? expression on the survival of GC patients and GC cell lines were examined with the Gene Expression Omnibus database and by siRNA of FOLR?. RNA-sequencing and Microarray analysis was conducted to identify the function of FOLR?. Proteins that interact with FOLR? were identified with shotgun LC-MS/MS. The antitumor efficacy of the anti-FOLR? 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.FOLR? was detected both at the cell membrane and in the cytoplasm. Shorter overall survival was associated with FOLR? expression in GC patients, whereas reduction of FOLR? attenuated cell proliferation without inducing cell death in GC cell lines. Transcriptomic and proteomic examinations revealed that the FOLR?-expressing cancer cells possess a mechanism of chemotherapy resistance supported by MDM2, and FOLR? indirectly regulates it through a chaperone protein prohibitin2 (PHB2). Although reduction of FOLR? 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.The ADC could be a more reasonable choice than mAb as a targeting agent for the FOLR?-expressing tumor.
Mesh Terms:
Animals, Antibodies, Monoclonal, Humanized, Antineoplastic Agents, Apoptosis, Biomarkers, Tumor, Cell Proliferation, Drug Resistance, Neoplasm, Female, Folate Receptor 1, Furans, Gene Expression Regulation, Neoplastic, Humans, Ketones, Mice, Mice, Inbred BALB C, Mice, Nude, Oxaliplatin, Prognosis, Prohibitins, Proteome, Proto-Oncogene Proteins c-mdm2, Stomach Neoplasms, Survival Rate, Transcriptome, Tumor Cells, Cultured, Xenograft Model Antitumor Assays
Clin Transl Med
Date: Dec. 01, 2020
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