Proteolysis targeting chimeric molecules as therapy for multiple myeloma: efficacy, biomarker and drug combinations.

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Proteolysis targeting chimeric molecules as therapy for multiple myeloma: efficacy, biomarker and drug combinations.

Haematologica. 2019 Jan 03;:

Authors: Lim SL, Damnernsawad A, Shyamsunder P, Chng WJ, Han BC, Xu L, Pan J, Pravin DP, Alkan S, Tyner JW, Koeffler HP

Abstract
Proteolysis targeting chimeric molecule ARV 825 causes ubiquitination of Bromodomains resulting in their efficient degradation by proteasome activity. Bromodomain degradation downregulates MYC transcription contributing to growth inhibition of various human cancers. We examined therapeutic potential of ARV 825 against multiple myeloma cells both in vitro and in vivo. ARV 825 in a dose-dependent manner inhibited proliferation of 13 human multiple myeloma cell lines and 3 fresh patient samples, associated with cell cycle arrest and apoptosis. ARV 825 degraded rapidly and efficiently BRD 2 and BRD 4. Sensitivity of multiple myeloma cells to ARV 825 was positively correlated with cereblon levels. RNA sequencing analysis showed important genes such as CCR1, RGS, MYB and MYC were downregulated by ARV 825. 170 small molecule inhibitors were screened for synergy with ARV 825. Combination of ARV 825 with inhibitor of either dual PI3K/mTOR, CRM1, VEGFR, PDGFRα/β, FLT3, IGF-1R, protein kinase C, CBP-EP300 or JAK1/2 showed synergistic activity. Importantly, ARV 825 significantly inhibited the growth of multiple myeloma xenografts and improved survival of the mice. Taken together, our results in conjunction with recently published findings provide a rationale for investigating the efficacy of ARV 825 for multiple myeloma, use of cereblon as a biomarker for therapy of multiple myeloma patients, as well as the combination of ARV 825 with small molecule inhibitors to improve the outcome of multiple myeloma patients.

PMID: 30606790 [PubMed - as supplied by publisher]

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