Person: Chauhan, Dharminder
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Chauhan
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Dharminder
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Chauhan, Dharminder
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Publication Development and Preclinical Validation of a Novel Covalent Ubiquitin Receptor Rpn13 Degrader in Multiple Myeloma(Springer Science and Business Media LLC, 2019-04-08) Song, Yan; Wu, Lei; Ray, Arghya; Li, Deyao; Du, Ting; Qi, Jun; Chauhan, Dharminder; Park, Paul; Picaud, Sarah; Wimalasena, Virangika; Filippakopoulos, Panagis; Anderson, KennethProteasome inhibition is an effective treatment for multiple myeloma (MM); however, targeting different components of the ubiquitin–proteasome system (UPS) remains elusive. Our RNA-interference studies identified proteasome-associated ubiquitin-receptor Rpn13 as a mediator of MM cell growth and survival. Here, we developed the first degrader of Rpn13, WL40, using a small-molecule-induced targeted protein degradation strategy to selectively degrade this component of the UPS. WL40 was synthesized by linking the Rpn13 covalent inhibitor RA190 with the cereblon (CRBN) binding ligand thalidomide. We show that WL40 binds to both Rpn13 and CRBN and triggers degradation of cellular Rpn13, and is therefore first-in-class in exploiting a covalent inhibitor for the development of degraders. Biochemical and cellular studies show that WL40-induced Rpn13 degradation is both CRBN E3 ligase- and Rpn13-dependent. Importantly, WL40 decreases viability in MM cell lines and patient MM cells, even those resistant to bortezomib. Mechanistically, WL40 interrupts Rpn13 function and activates caspase apoptotic cascade, ER stress response and p53/p21 signaling. In animal model studies, WL40 inhibits xenografted human MM cell growth and prolongs survival. Overall, our data show the development of the first UbR Rpn13 degrader with potent anti-MM activity, and provide proof of principle for the development of degraders targeting components of the UPS for therapeutic application.Publication Proteomic Analysis Identifies Mechanism(s) of Overcoming Bortezomib-Resistance via Targeting Ubiquitin Receptor Rpn13(American Society of Hematology, 2018-05-18) Du, Ting; Song, Yan; Ray, Arghya; Chauhan, Dharminder; Anderson, KennethOur prior study showed that inhibition of 19S proteasome-associated ubiquitin receptor Rpn13 can overcome bortezomib-resistance in MM cells. Here, we performed proteomic analysis of Rpn13 inhibitor (RA190)-treated MM cells and identified an antioxidant enzyme superoxide dismutase (SOD1) as a mediator of Rpn13 signaling. SOD1 levels are higher in MM patient cells versus normal PBMCs; and importantly, SOD1 expression correlates with the progression of disease and shorter survival. Functional validation studies show that RA190-induced cytotoxicity in bortezomib-sensitive and -resistant MM cells is associated with decrease in SOD1 levels; conversely, forced expression of SOD1 inhibits RA190-induced cell death. Genetic knockdown and biochemical blockade of SOD1 with LCS-1 sensitizes bortezomib-resistant MM cells to bortezomib. SOD1 inhibitor LCS-1 decreases viability in MM cell lines and patient cells. LCS-1-induced cell death is associated with: (i) increase in superoxide and ROS levels; (ii) activation of caspases, and p53/p21 signaling; (iii) decrease in MCL-1, BCL2, CDC2, cyclin B1 and c-Myc; (iv) ER stress response; and (v) inhibition of proteasome function. In animal model studies, LCS-1 inhibits xenografted bortezomib-resistant human MM cell growth and prolongs host survival. Our studies therefore show that targeting Rpn13 overcomes bortezomib-resistance by decreasing cellular SOD1 levels, and provide the rationale for novel therapeutics targeting SOD1 to improve patient outcome in MM.Publication Combination of a Selective HSP90α/β Inhibitor and a RAS-RAF-MEK-ERK Signaling Pathway Inhibitor Triggers Synergistic Cytotoxicity in Multiple Myeloma Cells(Public Library of Science, 2015) Suzuki, Rikio; Kikuchi, Shohei; Harada, Takeshi; Mimura, Naoya; Minami, Jiro; Ohguchi, Hiroto; Yoshida, Yasuhiro; Sagawa, Morihiko; Gorgun, Gullu; Cirstea, Diana; Cottini, Francesca; Jakubikova, Jana; Tai, Yu-Tzu; Chauhan, Dharminder; Richardson, Paul; Munshi, Nikhil; Ando, Kiyoshi; Utsugi, Teruhiro; Hideshima, Teru; Anderson, KennethHeat shock protein (HSP)90 inhibitors have shown significant anti-tumor activities in preclinical settings in both solid and hematological tumors. We previously reported that the novel, orally available HSP90α/β inhibitor TAS-116 shows significant anti-MM activities. In this study, we further examined the combination effect of TAS-116 with a RAS-RAF-MEK-ERK signaling pathway inhibitor in RAS- or BRAF-mutated MM cell lines. TAS-116 monotherapy significantly inhibited growth of RAS-mutated MM cell lines and was associated with decreased expression of downstream target proteins of the RAS-RAF-MEK-ERK signaling pathway. Moreover, TAS-116 showed synergistic growth inhibitory effects with the farnesyltransferase inhibitor tipifarnib, the BRAF inhibitor dabrafenib, and the MEK inhibitor selumetinib. Importantly, treatment with these inhibitors paradoxically enhanced p-C-Raf, p-MEK, and p-ERK activity, which was abrogated by TAS-116. TAS-116 also enhanced dabrafenib-induced MM cytotoxicity associated with mitochondrial damage-induced apoptosis, even in the BRAF-mutated U266 MM cell line. This enhanced apoptosis in RAS-mutated MM triggered by combination treatment was observed even in the presence of bone marrow stromal cells. Taken together, our results provide the rationale for novel combination treatment with HSP90α/β inhibitor and RAS-RAF-MEK-ERK signaling pathway inhibitors to improve outcomes in patients with in RAS- or BRAF-mutated MM.Publication Antitumor activities of selective HSP90α/β inhibitor, TAS-116, in combination with bortezomib in multiple myeloma(2014) Suzuki, Rikio; Hidehsima, Teru; Mimura, Naoya; Minami, Jiro; Ohguchi, Hiroto; Kikuchi, Shohei; Yoshida, Yasuhiro; Gorgun, Gullu; Cirstea, Diana; Cottini, Francesca; Jakubikova, Jana; Tai, Yu-Tzu; Chauhan, Dharminder; Richardson, Paul; Munshi, Nikhil; Utsugi, Teruhiro; Anderson, KennethPublication A Novel Hypoxia-Selective Epigenetic Agent RRx-001 Triggers Apoptosis and Overcomes Drug Resistance in Multiple Myeloma Cells(2016) Das, Deepika Sharma; Ray, Arghya; Das, Abhishek; Song, Yan; Oronsky, Bryan; Richardson, Paul; Scicinski, Jan; Chauhan, Dharminder; Anderson, KennethThe hypoxic bone-marrow (BM) microenvironment confers growth/survival and drug-resistance in multiple myeloma (MM) cells. Novel therapies targeting the MM cell in its hypoxic-BM milieu may overcome drug resistance. Recent studies led to the development of a novel molecule RRx-001 with hypoxia-selective epigenetic and Nitric Oxide-donating properties. Here we demonstrate that RRx-001 decreases the viability of MM cell lines and primary patient cells, as well as overcomes drug-resistance. RRx-001 inhibits MM cell growth in the presence of BM stromal cells. RRx-001 induced apoptosis is associated with: 1) activation of caspases; 2) release of ROS and nitrogen-species; 3) induction of DNA damage via ATM/γ-H2AX; and 4) decrease in DNA methytransferase (DNMT) and global methylation. RNA interference study shows a predominant role of DNMT1 in MM cell survival versus DNMT3a or DNMT3b. Deubiquitylating enzyme USP7 stimulates DNMT1 activity; and conversely, USP7-siRNA reduced DNMT1 activity and decreased MM cell viability. RRx-001 plus USP7 inhibitor P5091 triggered synergistic anti-MM activity. MM xenograft studies show that RRx-001 is well tolerated, inhibits tumor growth, and enhances survival. Combining RRx-001 with pomalidomide, bortezomib or SAHA induces synergistic anti-MM activity. Our results provide the rationale for translation of RRx-001, either alone or in combination, to clinical evaluation in MM.Publication Targeting the UPS as Therapy in Multiple Myeloma(BioMed Central, 2008) Chauhan, Dharminder; Bianchi, Giada; Anderson, KennethThe coordinated regulation of cellular protein synthesis and degradation is essential for normal cellular functioning. The ubiquitin proteasome system mediates the intracellular protein degradation that is required for normal cellular homeostasis. The 26S proteasome is a multi-enzyme protease that degrades redundant proteins; conversely, inhibition of proteasomal degradation results in intracellular aggregation of unwanted proteins and cell death. This observation led to the development of proteasome inhibitors as therapeutics for use in cancer. The clinical applicability of targeting proteasomes is exemplified by the recent FDA approval of the first proteasome inhibitor, bortezomib, for the treatment of relapsed/refractory multiple myeloma. Although bortezomib represents a major advance in the treatment of this disease, it can be associated with toxicity and the development of drug resistance. Importantly, extensive preclinical studies suggest that combination therapies can both circumvent drug resistance and reduce toxicity. In addition, promising novel proteasome inhibitors, which are distinct from bortezomib, and exhibit equipotent anti-multiple myeloma activities, are undergoing clinical evaluation in order to improve patient outcome in multiple myeloma. Republished from Current BioData's Targeted Proteins database (TPdb; http://www.targetedproteinsdb.com).Publication Identification and Validation of Ecto-5' Nucleotidase as an Immunotherapeutic Target in Multiple Myeloma(Springer Science and Business Media LLC, 2022-04-01) Ray, Arghya; Song, Yan; Du, Ting; Buon, Leutz; Tai, Yu-Tzu; Chauhan, Dharminder; Anderson, KennethInteraction of plasmacytoid dendritic cells (pDCs) with multiple myeloma (MM) cells, T- or NK-effector cells in the bone marrow (BM) microenvironment induces tumor cell growth, as well as inhibits innate and adaptive immune responses. Defining pDC-MM interaction-triggered immunosuppressive mechanism(s) will enable design of interventional therapies to augment anti-MM immunity. In the present study, we show that pDC-MM interactions induce metabolic enzyme Ecto-5’ Nucleotidase/CD73 in both pDCs and MM cells. Gene expression database from MM patients showed that CD73 levels inversely correlates with overall survival. Using our pDC-MM coculture models, we found that blockade of CD73 with anti-CD73 Abs: decreases adenosine levels; activates MM patient pDCs; and triggers cytotoxic T lymphocytes (CTL) activity against autologous patient MM cells. Combination of anti-CD73 Abs and an immune-stimulating agent TLR-7 agonist enhances autologous MM-specific CD8+ CTL activity. Taken together, our preclinical data suggest that the therapeutic targeting of CD73, alone or in combination with TLR-7 agonist, represents a promising novel strategy to restore host anti-MM immunity.Publication Preclinical Validation of Alpha-Enolase (ENO1) As a Novel Immunometabolic Target in Multiple Myeloma(Springer, 2020-02-05) Ray, Arghya; Song, Yan; Chauhan, Dharminder; Anderson, KennethBone marrow plasmacytoid dendritic cells (pDCs) in patients with multiple myeloma (MM) promote tumor growth, survival, drug resistance, and immune suppression. Understanding the molecular signaling crosstalk among the tumor cells, pDCs and immune cells will identify novel therapeutic approaches to enhance anti-MM immunity. Using oligonucleotide arrays, we found that pDC-MM interactions induce metabolic enzyme Alpha-Enolase (ENO1) in both pDCs and MM cells. Analysis of MM patient gene expression profiling database showed that ENO1 expression inversely correlates with overall survival. Protein expression analysis showed that ENO1 is expressed in pDC and MM cells; and importantly, that pDC-MM coculture further increases ENO1 expression in both MM cells and pDCs. Using our coculture models of patient autologous pDC-T-NK-MM cells, we examined whether targeting ENO1 can enhance anti-MM immunity. Biochemical inhibition of ENO1 with ENO inhibitor (ENOi) activates pDCs, as well as increases pDC-induced MM-specific CD8+ CTL and NK cell activity against autologous tumor cells. Combination of ENO1i and anti-PD-L1 Ab or HDAC6i ACY-241 enhances autologous MM-specific CD8+ CTL activity. Our preclinical data therefore provide the basis for novel immune-based therapeutic approaches targeting ENO1, alone or in combination with anti-PD-L1 Ab or ACY241, to restore anti-MM immunity, enhance MM cytotoxicity, and improve patient outcome.Publication Targeting Tryptophan Catabolic Kynurenine Pathway Enhances Antitumor Immunity and Cytotoxicity in Multiple Myeloma(Springer Science and Business Media LLC, 2019-08-28) Ray, Arghya; Song, Yan; Du, Ting; Tai, Yu-Tzu; Chauhan, Dharminder; Anderson, Kenneth