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• W2980391423 abstract "Heterobifunctional proteolysis-targeting chimeric (PROTAC) compounds exhibit potent preclinical activity against multiple myeloma (MM) and other neoplasias by reprogramming” E3 ligases to ubiquitinate and cause degradation of target oncoproteins. The mechanisms regulating MM cell sensitivity to different classes of these PROTACs are incompletely understood. To address this topic, we performed CRISPR studies (at genome-scale and with individual sgRNAs) to define genes whose editing (loss-of-function, LOF) or activation (gain-of-function, GOF) confer MM cell resistance to PROTACs that target oncoproteins (e.g., BET bromodomain, CDK9) through different E3 ligases (e.g. CRBN, VHL, MDM2). We also examined the patterns of cross-resistance between these PROTACs, in experiments whereby cell populations surviving from a genome-scale CRISPR study with one class of PROTACs were sequentially exposed to other PROTACs that engaged the same or different E3 ligases and/or oncoproteins. Through these studies, we observed that MM cell resistance to CRBN- or VHL-based PROTACs does not involve genes whose LOF confers high-risk in MM patients (e.g. TP53, PTEN, negative regulators of cell cycle, et.c.), suggesting that PROTACs may be active in the context of MM with adverse genomic features. Resistance to all PROTACs studied so far primarily involves prevention of, rather than adaptation to, breakdown of the target oncoprotein and involves e.g. LOF for the cognate E3 ligase or regulators of the respective cullin-RING ligase (CRL) complex. MM cells resistant to CRBN-based PROTACs were enriched for LOF of CRBN and, to a lesser extent, regulators of its CRL-CUL4A, including COP9 signalosome genes, DDB1 or the E2 enzyme UBE2G1. MM cells resistant to VHL-based PROTACs were enriched for LOF of CUL2, VHL itself, and other CUL2-VHL interactors (e.g. RBX1, TCEB1, TCEB2, UBE2R2) and LOF of COP9 signalosome genes is less protective against VHL- (vs. CRBN-) based PROTACs: these differences reflect different composition/regulation of CUL4A-CRBN vs. CUL2-VHL. MDR1 transporter (ABCB1) is the sole gene so far whose GOF is associated with resistance to any PROTAC we tested. PROTACs engaging the same E3 ligase but different oncoproteins can exhibit synergy with simultaneous, but cross-resistance with sequential, administration. PROTACs engaging different E3 ligases/CRLs but the same oncoprotein can exhibit antagonism with simultaneous, but overcome cross-resistance with sequential, administration. Our observations have major implications for the development of new PROTACs and the clinical testing of different classes of PROTACs, as single-agents or in combination with established anti-MM agents, including CRBN-binding thalidomide derivatives, or other PROTACs." @default.
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• W2980391423 date "2019-10-01" @default.
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• W2980391423 title "Molecular markers of myeloma cell sensitivity vs. resistance to heterobifunctional degraders of oncoproteins: therapeutic implications." @default.
• W2980391423 doi "https://doi.org/10.1016/j.clml.2019.09.222" @default.
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