TY - JOUR T1 - NPEPPS regulates intracellular import and sensitivity to cisplatin by interaction with volume regulated anion channels JF - bioRxiv DO - 10.1101/2021.03.04.433676 SP - 2021.03.04.433676 AU - Robert T. Jones AU - Andrew Goodspeed AU - Maryam C. Akbarzadeh AU - Mathijs Scholtes AU - Hedvig Vekony AU - Annie Jean AU - Charlene B. Tilton AU - Saswat Mohapatra AU - Michael V. Orman AU - Stephanie Araki AU - Molishree Joshi AU - Mahmood Javaid AU - Eric T. Clambey AU - Ryan Layer AU - Teemu D. Laajala AU - Sarah Parker AU - Tokameh Mahmoudi AU - Tahlita Zuiverloon AU - Dan Theodorescu AU - James C. Costello Y1 - 2021/01/01 UR - http://biorxiv.org/content/early/2021/06/19/2021.03.04.433676.abstract N2 - Despite routine use of platinum-based chemotherapeutics in cancer treatment, there remains a need to improve efficacy and patient selection. Multi-omic assessment of human bladder cancer cell lines and their cisplatin resistant derivatives and whole-genome CRISPR screens identified NPEPPS, the puromycin-sensitive aminopeptidase as a novel driver of cisplatin resistance. NPEPPS depletion increased cisplatin import and sensitization of resistant cells in vitro and in vivo. Pharmacologic inhibition of NPEPPS in cells and chemoresistant, patient-derived tumor organoids improved response to cisplatin. NPEPPS was found in complex with volume regulated anion channel (VRAC) subunits LRRC8A and LRRC8D, whose loss is known to enhance resistance to cisplatin. Depletion of LRRC8A the only obligate subunit for normal VRAC function abrogated the effect of NPEPPS-mediated cisplatin import. Our findings describe the first mechanism by which VRACs can be targeted for therapeutic benefit.HIGHLIGHTSMulti-omic screening found NPEPPS is a driver of cisplatin resistance in cancerNPEPPS is in protein complex with LRRC8A and D, volume regulated anion channel (VRAC) subunitsLRRC8A and D loss increases cisplatin resistance and reduce its intracellular levelsNPEPPS regulates cisplatin import and sensitivity through VRACsNPEPPS function is inhibited by small molecules offering potential for clinical translationCompeting Interest StatementA provisional patent 63/153,519 has been filed on the subject matter of this work. J.C.C. is co-founder of PrecisionProfile. All other authors declare no competing interests. ER -