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Plasma Cell Disorders
Proteolysis targeting chimeric molecules as therapy for multiple myeloma: efficacy, biomarker and drug combinations
Ferrata Storti Foundation
Haematologica 2019 Volume 104(6):1209-1220
Su Lin Lim,1* Alisa Damnernsawad,2* Pavithra Shyamsunder,3 Wee Joo Chng,3 Bing Chen Han,1 Liang Xu,3 Jian Pan,1 Dakle Pushkar Pravin,3 Serhan Alkan,1 Jeffrey W. Tyner2** H. Phillip Koeffler1,3**
1Cedars Sinai Medical Center, Los Angeles, CA, USA; 2Division of Hematology and Medical Oncology, Oregon Health and Science University Knight Cancer Institute, Portland, OR, USA and 3Cancer Science Institute of Singapore, National University of Singapore, Singapore
*SLL and AD contributed equally to this work. **JWT and HPK contributed equally to this work.
ABSTRACT
Proteolysis targeting chimeric molecule ARV 825 causes ubiquitination of bromodomains resulting in their efficient degradation by protea- some activity. Bromodomain degradation down-regulates MYC tran- scription contributing to growth inhibition of various human cancers. We examined the therapeutic potential of ARV 825 against multiple myeloma (MM) cells both in vitro and in vivo. In a dose-dependent manner, ARV 825 inhibited proliferation of 13 human MM cell lines and three fresh patient samples, and was associated with cell cycle arrest and apoptosis. ARV 825 rapidly and efficiently degraded BRD 2 and BRD 4. Sensitivity of MM cells to ARV 825 was positively correlated with cereblon levels. RNA sequencing analysis showed important genes such as CCR1, RGS, MYB and MYC were down-regulated by ARV 825. A total of 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/b, FLT3, IGF-1R, protein kinase C, CBP-EP300 or JAK1/2 showed synergistic activi- ty. Importantly, ARV 825 significantly inhibited the growth of MM xenografts and improved mice survival. Taken together, our results, in con- junction with recently published findings, provide a rationale for investigat- ing the efficacy of ARV 825 for MM, use of cereblon as a biomarker for ther- apy of MM patients, and the combination of ARV 825 with small molecule inhibitors to improve the outcome of MM patients.
Introduction
Multiple myeloma (MM) is characterized by neoplastic proliferation of clonal plas- ma cells producing a monoclonal immunoglobulin. It accounts for more than 17% of hematologic malignancies in the US.1 Over the past decade, newly introduced ther- apeutic regimens (e.g. proteasome inhibitor and immunomodulatory drugs) have sig- nificantly improved treatment outcome and survival of MM. Nevertheless, most of these patients eventually relapse, underlining the need for new therapeutic approach- es. Agents with novel mechanism of action such as monoclonal antibodies (e.g. dara- tumumab, elotuzumab), histone deacetylase inhibitors, kinesin spindle protein inhibitors, and cereblon modulator iberdomide are under ongoing investigation for treating MM. Other than that, chimeric antigen receptor T (CAR-T) cells directed against B-cell maturation antigen (BCMA) have shown promising tumor cell reduc- tion in MM.2 The search for novel agents is rapidly expanding and this, together with identification of novel combinations, should help revolutionize treatment of this dis- ease.
Bromodomains (BRD) 2, 3 and 4, and T are members of the bromodomain extrater- minal domain (BET) family facilitating transcriptional activation by RNA polymerase II.3 BRD 2, 3 and 4 bind to acetylated chromatin promoting progression from G1 to
Correspondence:
SU LIN LIM
sulin_lim_86@hotmail.com
Received: July 11, 2018. Accepted: January 2, 2019. Pre-published: January 3, 2019.
doi:10.3324/haematol.2018.201483
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/104/6/1209
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