Abstract P177: NPEPPS regulates cisplatin-resistance and can be targeted to overcome treatment resistance in patient-derived bladder cancer tumoroids

Abstract

Abstract Gemcitabine/cisplatin combination is the recommended neoadjuvant chemotherapy (NAC) for muscle-invasive bladder cancer (MIBC) patients undergoing surgical removal of the bladder (cystectomy). Patients without residual tumor at cystectomy ,complete pathological response (pCR), have a good 5-yr OS of 80%. However, due to NAC resistance, only 25% of the patients achieve a pCR. This study aims to increase the number of patients reaching pCR by discovery and functional interrogation of novel and pharmacologically targetable mechanisms causal to NAC resistance. We have identified an M1 aminopeptidase, NPEPPS, to regulate intracellular cisplatin import through volume regulated anion channels (VRACs). We show that genetic inhibition of NPEPPS increases the intracellular concentrations of cisplatin, hereby re-sensitizing gem/cis-resistant BC cell lines. On the other side, NPEPPS over-expression enhanced resistance to cisplatin. Pharmacological inhibition of NPEPPS with tosedostat results re-sensitization of gem/cis resistant BC cells in vitro and in vivo. Additional therapeutically validation was performed in gem/cis resistant patient-derived tumoroids. For this purpose, tumoroid cultures were generated from bladder cancer patients whom did not respond to pre-operative gem/cis, molecularly characterized and compared to the tumor of origin. Comparison of bladder cancer specific hotspot mutations, copy-number aberrations and H&E staining confirmed that patient-specific tumor traits were maintained in ex vivo tumoroid cultures. Moreover, tumoroid cultures generated from NAC-resistant patients were also resistant to cisplatin concentrations that exceeded physiological serum concentrations. Interestingly, addition of NPEPPS-inhibitor tosedostat sensitized these NAC resistant tumoroids to serum concentrations of cisplatin. These findings have potential for rapid translation into the clinic and invite trials investigating tosedostat to overcome chemoresistance. Citation Format: Mathijs P. Scholtes, Maryam Akbarzadeh, Dan Theodorescu, James C. Costello, Tokameh Mahmoudi, Tahlita C.M. Zuiverloon. NPEPPS regulates cisplatin-resistance and can be targeted to overcome treatment resistance in patient-derived bladder cancer tumoroids [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P177.