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Synthetic IDE inhibitors sensitize and reverse acquired resistance of multiple myeloma cells to proteasome inhibitors

ABSTRACT: Synthetic IDE inhibitors sensitize and reverse acquired resistance of multiple myeloma cells to proteasome inhibitors

PROVIDER: PRJNA763933 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR15925219_1.fastq.gz	Fastqsanger.gz
	SRR15925219_2.fastq.gz	Fastqsanger.gz
	SRR15925220_1.fastq.gz	Fastqsanger.gz
	SRR15925220_2.fastq.gz	Fastqsanger.gz
	SRR15925221_1.fastq.gz	Fastqsanger.gz

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Synthetic IDE inhibitors sensitize and reverse acquired resistance of multiple myeloma cells to proteasome inhibitors

Project description:The use of proteasome inhibitors (PIs) is the backbone of multiple myeloma (MM) treatment. However, almost all MM patients who initially respond to PIs eventually develop resistance to these drugs. The discovery of a pharmacological intervention that increase the potency of PIs in order to reduce their dose and/or restore the sensitivity of MM cells to PIs is an important avenue in MM research. Insulin Degrading Enzyme (IDE) is a druggable protease known to modulate proteasome. We show here that, in two independent cohorts, a high expression of IDE in cells from MM patients is associated with shorter overall survival. Likewise, we designed specific, cell permeable, IDE inihibitors and showed that full pharmacological engagement of IDE is associated with enhanced sensitivity to PIs of MM cell lines, as well as of primary patient MM cells. Furthermore, treatment of PI-resistant MM cells with the inhibitor overcomes their resistance to PI. Finally we designed an improved IDE inhibitor suitable for in vivo pharmacology. This inhibitor which develops multiple interactions with IDE at the catalytic site and display good pharmacocinetic properties, boosts the anti-myeloma potency of bortezomib in a syngenic mouse model of MM. In vitro, it appears that IDE inhibition reduces the residual proteasome activty in PI-treated cells and increases the apoptotic potency of carfilzomib through induction of an Integrated Stress Response associated with strongly reduced IGF1 and IGF1R expressions. The pharmacological profile of this new combination appears highly desirable for the treatment of MM.

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Project description:Epigenetic modifying enzymes are commonly mutated in diffuse large B cell lymphoma (DLBCL). Importantly, genetics abnormalities lead to inactivation of HAT, which tilt the balance in favor of decreased protein acetylation in DLBCL cells. This suggests that protein acetylation regulation is an important factor in DLBCL pathogenesis and a potential target for therapy. We developed resistant cell lines to the histone deacetylase inhibitor (HDACi) vorinostat, in order to better define molecular mechanisms of action of HDACi in lymphoma cells. We found that cells resistant to HDACi have increased protein synthesis and proteasomal degradation. Additionally, cells resistant to HDACi have acquired increased susceptibility to proteasome inhibitors and this correlates with activation of the unfolded protein response. Importantly, using transcriptional signatures found in our resistant lymphoma cell line model, we show that tumors from DLBCL patients treated but unresponsive to HDACi therapy undergo similar changes. Together, these data show, for the first time, that HDACi may be used to prime DLBCL for targeted therapy including proteasome inhibitors. Gene expression in U937 cells after 12h exposure to 2ÂµM vorinostat and after development of resistance to 2 ÂµM vorinostat, with and without vorinostat in the media.

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