November-December 2019, Volume 16, Issue 6
RewIRE(1α)ing the Unfolded Protein Response in Multiple Myeloma
Published on: October 08, 2019
Harnoss JM, Le Thomas A, Shemorry A, et al. Disruption of IRE1α through its kinase domain attenuates multiple myeloma. Proc Natl Acad Sci U S A. 2019;116:16420-16429.
Despite ongoing efforts for novel therapeutic agents for multiple myeloma (MM), the standard-of-care regimens have heavily relied on proteasome inhibitors (PIs) and immunomodulatory agents (IMiDs) for more than a decade. While there are numerous investigational agents in the clinic, the heterogeneity across all MM subtypes has heavily stalled the success of novel therapeutic agents.
MM is the second most common hematologic cancer and is classified by the bone marrow infiltration of malignant monoclonal immunoglobulin (Ig) -secreting plasma cells. While clinical features, including CRAB (calcium [elevated], renal failure, anemia, and bone lesions/pain) symptoms, M-spike, and plasma cell infiltration levels (BMPC), are commonly used to stratify patients’ disease stage, the underlying molecular mechanisms of pathogenesis are often overlooked for targeted therapies.1 There are current efforts to genetically stratify therapies; for instance the BCL2 inhibitor venetoclax is undergoing phase III clinical trials for a specific subset of patients with MM who harbor the t(11;14) translocation.2 However, the use of PIs in MM treatment has been effective across all myeloma subtypes, mainly due to leveraging the biology of Ig-secreting plasma cells. Upon elevated demand for Ig secretion, insufficient endoplasmic reticulum (ER) capacity results in the accumulation of unfolded proteins (UPs). Inhibition of the 26S proteasome by PIs creates a backlog of substrates that cannot be effectively degraded, activating the UP response (UPR) and ultimately leading to apoptosis.3 Thus, the UPR may serve as potential therapeutic vulnerability across all subsets of patients with MM. One of three ER stress sensors, inositol-requiring enzyme 1-α (IRE1α), helps detect UP and alleviate ER stress from the newly increased demand of secreted Igs. IRE1α contains a cytosolic kinase domain and tandem endoribonuclease (RNase) domain, which upon activation, cleaves mRNA coding unspliced X-box protein 1 (XBP1u). Upon mRNA cleavage, the newly translated XBP1 stimulates numerous genes needed to alleviate the UPR, including protein chaperones and disulfide isomerases.4,5
In a recent article, Dr. Jonathan Harnoss and colleagues genetically and pharmacologically targeted IRE1α and the UPR in MM. The authors showed that a panel of genetically diverse cell lines all harbor IRE1α, and genetic disruption of IRE1α, or downstream XBP1, attenuates tumor growth in MM xenograph mouse models. Pharmacologic targeting of the IRE1α kinase domain was achieved through selective small-molecule inhibitors as previously reported. Interestingly, these selective inhibitors also attenuated IRE1α ribonuclease activity (and further spliced XBP1u mRNA) via a conformational change of the kinase domain (specifically the αC-helix) as determined by X-ray crystallography. This conformational change ultimately afforded allosteric inhibition of IRE1α’s RNase activity. Previous targeting of IRE1α shows that ATP competitive inhibitors, which do not stabilize a conformational change of the αC-helix (type I and type II inhibitors), can maintain or in some cases activate IRE1α’s ribonuclease activity.6,7 Using these highly selective inhibitors of both IRE1α’s kinase and ribonuclease domains, the authors further show that pharmacologic targeting of IRE1α can attenuate subcutaneous and orthometastatic growth of human MM xenografts in severe combined immunodeficient mice. Furthermore, these compounds can selectively target CD138+ ex vivo MM cells with superior selectivity to nonmalignant CD138– cells. Thus, providing evidence that targeting the UPR via IRE1α may be a successful strategy across all subsets of MM patients.
Since a cure for MM does not exist, novel therapeutic strategies are essential for prolonged survival and favorable clinical outcomes. As we unravel the genomic complexities and molecular mechanisms that govern pathogenesis, novel targeted therapies can follow. PIs, however, are among the most successful agents for MM treatment to date, due in part to their genomically indiscriminate efficacy. They take advantage of a vulnerability of the UPR in highly Ig-secreting plasma cells. This strategy has provided prolonged survival across this heterogenous disease and suggests a unique mechanism to develop therapies that can be advantageous across multiple MM subtypes. The findings provided by Dr. Harnoss and colleagues offer evidence that targeting the UPR via IRE1α may be a successful therapeutic strategy and further show its compatibility and synergy with standard-of-care PIs. Of note, these inhibitors also have the unique ability to target distal allosteric sites of IRE1α, showcasing the ability to perturb both catalytic and distal protein domains of kinases simultaneously with a single agent. As kinases have been a successful therapeutic target across all cancers, this phenomenon of targeting noncatalytic functions is still in its infancy and can provide kinase inhibitors with enhanced efficacy.8 Therefore, as IRE1α inhibitors make their way to the clinic, both selectivity and impact on allostery should be thoroughly investigated. Therapeutic strategies that can target all myeloma subtypes are still feasible and may rely upon modulating the UPR axis. Ultimately, it is still unclear whether the next standard-of-care treatments will be tailored targeted therapies, pan-MM agents, or some combination of the two. However, a highly heterogenous disease may require a heterogenous drug-toolbox, and selective IRE1α inhibitors are the newest addition.
Kyle RA, Rajkumar SV. Criteria for diagnosis, staging, risk stratification and response assessment of multiple myeloma. Leukemia. 2009;23:3-9.
Kumar S, Kaufman JL, Gasparetto C, et al. Efficacy of venetoclax as targeted therapy for relapsed/refractory t(11;14) multiple myeloma. Blood. 2017;130:2401-2409.
Rückrich T, Kraus M, Gogel J, et al. Characterization of the ubiquitin-proteasome system in bortezomib-adapted cells. Leukemia. 2009;23:1098-1105.
Calfon M, Zeng H, Urano F, et al. IRE1 couples endoplasmic reticulum load to secretory capacity by processing the XBP-1 mRNA. Nature. 2002;415:92-96.
Ron D, Hubbard SR. How IRE1 reacts to ER stress.. Cell. 2008;132:24-26.
Wang L, Perera BG, Hari SB, et al. Divergent allosteric control of the IRE1α endoribonuclease using kinase inhibitors. Nat Chem Biol. 2012;8:982-989.
Maly DJ, Papa FR. Druggable sensors of the unfolded protein response. Nat Chem Biol. 2014;10:892-901.
Kung JE, Jura N. Structural basis for the non-catalytic functions of protein kinases. Structure. 2016;24:7-24.
Conflict of Interests
Drs. Agius, Tahri, and Ghobrial indicated no relevant conflicts of interest.
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