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Article ; Online: BCMA-targeted bortezomib nanotherapy improves therapeutic efficacy, overcomes resistance, and modulates the immune microenvironment in multiple myeloma.

Dutta, Debasmita / Liu, Jiye / Wen, Kenneth / Kurata, Keiji / Fulciniti, Mariateresa / Gulla, Annamaria / Hideshima, Teru / Anderson, Kenneth C

Blood cancer journal

2023 Volume 13, Issue 1, Page(s) 184

Abstract: Bortezomib (BTZ) is a standard-of-care treatment in multiple myeloma (MM); however, adverse side effects and development of resistance limit its long term benefit. To improve target specificity, therapeutic efficacy, and overcome resistance, we designed ... ...

Abstract	Bortezomib (BTZ) is a standard-of-care treatment in multiple myeloma (MM); however, adverse side effects and development of resistance limit its long term benefit. To improve target specificity, therapeutic efficacy, and overcome resistance, we designed nanoparticles that encapsulate BTZ and are surface-functionalized with BCMA antibodies (BCMA-BTZ-NPs). We confirmed efficient cellular internalization of the BCMA-BTZ-NPs only in BCMA-expressing MM cells, but not in BCMA-knockout (KO) cells. In addition, BCMA-BTZ-NPs showed target-specific cytotoxicity against MM cell lines and primary tumor cells from MM patients. The BCMA-BTZ-NPs entered the cell through receptor-mediated uptake, which escapes a mechanism of BTZ resistance based on upregulating P-glycoprotein. Furthermore, BCMA-BTZ-NPs induced cell death more efficiently than non-targeted nanoparticles or free BTZ, triggering potent mitochondrial depolarization followed by apoptosis. In BTZ-resistant cells, BCMA-BTZ-NPs inhibited proteasome activity more effectively than free BTZ or non-targeted nanoparticles. Additionally, BCMA-BTZ-NPs enhanced immunogenic cell death and activated the autophagic pathway more than free BTZ. Finally, we found that BCMA-BTZ-NPs selectively accumulated at the tumor site in a murine xenograft model, enhanced tumor reduction, and prolonged host survival. These results suggest BCMA-BTZ-NPs provide a promising therapeutic strategy for enhancing the efficacy of BTZ and establish a framework for their evaluation in a clinical setting.
MeSH term(s)	Humans ; Animals ; Mice ; Bortezomib/pharmacology ; Bortezomib/therapeutic use ; Multiple Myeloma/pathology ; B-Cell Maturation Antigen ; Drug Resistance, Neoplasm ; Cell Line, Tumor ; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; Tumor Microenvironment
Chemical Substances	Bortezomib (69G8BD63PP) ; B-Cell Maturation Antigen ; Antineoplastic Agents
Language	English
Publishing date	2023-12-11
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2600560-8
ISSN	2044-5385 ; 2044-5385
ISSN (online)	2044-5385
ISSN	2044-5385
DOI	10.1038/s41408-023-00955-y
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: BRD9 Degradation Disrupts Ribosome Biogenesis in Multiple Myeloma.

Kurata, Keiji / Samur, Mehmet K / Liow, Priscilla / Wen, Kenneth / Yamamoto, Leona / Liu, Jiye / Morelli, Eugenio / Gulla, Annamaria / Tai, Yu-Tzu / Qi, Jun / Hideshima, Teru / Anderson, Kenneth C

Clinical cancer research : an official journal of the American Association for Cancer Research

2023 Volume 29, Issue 9, Page(s) 1807–1821

Abstract: Purpose: BRD9 is a defining component of the noncanonical SWI/SNF complex, which regulates gene expression by controlling chromatin dynamics. Although recent studies have found an oncogenic role for BRD9 in multiple cancer types including multiple ... ...

Abstract	Purpose: BRD9 is a defining component of the noncanonical SWI/SNF complex, which regulates gene expression by controlling chromatin dynamics. Although recent studies have found an oncogenic role for BRD9 in multiple cancer types including multiple myeloma, its clinical significance and oncogenic mechanism have not yet been elucidated. Here, we sought to identify the clinical and biological impact of BRD9 in multiple myeloma, which may contribute to the development of novel therapeutic strategies. Experimental design: We performed integrated analyses of BRD9 in vitro and in vivo using multiple myeloma cell lines and primary multiple myeloma cells in established preclinical models, which identified the molecular functions of BRD9 contributing to multiple myeloma cell survival. Results: We found that high BRD9 expression was a poor prognostic factor in multiple myeloma. Depleting BRD9 by genetic (shRNA) and pharmacologic (dBRD9-A; proteolysis-targeting chimera; BRD9 degrader) approaches downregulated ribosome biogenesis genes, decreased the expression of the master regulator MYC, and disrupted the protein-synthesis maintenance machinery, thereby inhibiting multiple myeloma cell growth in vitro and in vivo in preclinical models. Importantly, we identified that the expression of ribosome biogenesis genes was associated with the disease progression and prognosis of patients with multiple myeloma. Our results suggest that BRD9 promotes gene expression by predominantly occupying the promoter regions of ribosome biogenesis genes and cooperating with BRD4 to enhance the transcriptional function of MYC. Conclusions: Our study identifies and validates BRD9 as a novel therapeutic target in preclinical models of multiple myeloma, which provides the framework for the clinical evaluation of BRD9 degraders to improve patient outcome.
MeSH term(s)	Humans ; Transcription Factors/genetics ; Transcription Factors/metabolism ; Multiple Myeloma/genetics ; Nuclear Proteins/genetics ; Ribosomes/genetics ; Ribosomes/metabolism ; Cell Cycle Proteins
Chemical Substances	Transcription Factors ; Nuclear Proteins ; BRD4 protein, human ; Cell Cycle Proteins ; BRD9 protein, human
Language	English
Publishing date	2023-02-14
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1225457-5
ISSN	1557-3265 ; 1078-0432
ISSN (online)	1557-3265
ISSN	1078-0432
DOI	10.1158/1078-0432.CCR-22-3668
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Zs.A 4223: Show issues

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Article ; Online: Epigenetic regulation of CD38/CD48 by KDM6A mediates NK cell response in multiple myeloma.

Nature communications

2024 Volume 15, Issue 1, Page(s) 1367

Abstract: Anti-CD38 monoclonal antibodies like Daratumumab (Dara) are effective in multiple myeloma (MM); however, drug resistance ultimately occurs and the mechanisms behind this are poorly understood. Here, we identify, via two in vitro genome-wide CRISPR ... ...

Abstract	Anti-CD38 monoclonal antibodies like Daratumumab (Dara) are effective in multiple myeloma (MM); however, drug resistance ultimately occurs and the mechanisms behind this are poorly understood. Here, we identify, via two in vitro genome-wide CRISPR screens probing Daratumumab resistance, KDM6A as an important regulator of sensitivity to Daratumumab-mediated antibody-dependent cellular cytotoxicity (ADCC). Loss of KDM6A leads to increased levels of H3K27me3 on the promoter of CD38, resulting in a marked downregulation in CD38 expression, which may cause resistance to Daratumumab-mediated ADCC. Re-introducing CD38 does not reverse Daratumumab-mediated ADCC fully, which suggests that additional KDM6A targets, including CD48 which is also downregulated upon KDM6A loss, contribute to Daratumumab-mediated ADCC. Inhibition of H3K27me3 with an EZH2 inhibitor resulted in CD38 and CD48 upregulation and restored sensitivity to Daratumumab. These findings suggest KDM6A loss as a mechanism of Daratumumab resistance and lay down the proof of principle for the therapeutic application of EZH2 inhibitors, one of which is already FDA-approved, in improving MM responsiveness to Daratumumab.
MeSH term(s)	Humans ; Multiple Myeloma/drug therapy ; Multiple Myeloma/genetics ; Epigenesis, Genetic ; Histones/metabolism ; ADP-ribosyl Cyclase 1 ; Killer Cells, Natural
Chemical Substances	Histones ; ADP-ribosyl Cyclase 1 (EC 3.2.2.6)
Language	English
Publishing date	2024-02-14
Publishing country	England
Document type	Journal Article
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-024-45561-z
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Article ; Online: γ-secretase inhibitors augment efficacy of BCMA-targeting bispecific antibodies against multiple myeloma cells without impairing T-cell activation and differentiation.

Chen, Hailin / Yu, Tengteng / Lin, Liang / Xing, Lijie / Cho, Shih-Feng / Wen, Kenneth / Aardalen, Kimberly / Oka, Adwait / Lam, Joni / Daley, Mike / Lu, Haihui / Munshi, Nikhil / Anderson, Kenneth C / Tai, Yu-Tzu

Blood cancer journal

2022 Volume 12, Issue 8, Page(s) 118

Abstract: We here defined the impacts of γ-secretase inhibitors (GSIs) on T-cell-dependent BCMA-specific multiple myeloma (MM) cell lysis and immunomodulatory effects induced by bispecific antibodies (BisAbs). GSIs-induced membrane BCMA (mBCMA) accumulation ... ...

Abstract	We here defined the impacts of γ-secretase inhibitors (GSIs) on T-cell-dependent BCMA-specific multiple myeloma (MM) cell lysis and immunomodulatory effects induced by bispecific antibodies (BisAbs). GSIs-induced membrane BCMA (mBCMA) accumulation reached near maximum within 4 h and sustained over 42h-study period on MM cell lines and patient MM cells. GSIs, i.e., 2 nM LY-411575 or 1 μM DAPT, robustly increased mBCMA densities on CD138
MeSH term(s)	Amyloid Precursor Protein Secretases ; Animals ; Antibodies, Bispecific/therapeutic use ; B-Cell Maturation Antigen ; Humans ; Mice ; Multiple Myeloma/drug therapy ; T-Lymphocytes
Chemical Substances	Antibodies, Bispecific ; B-Cell Maturation Antigen ; Amyloid Precursor Protein Secretases (EC 3.4.-)
Language	English
Publishing date	2022-08-16
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2600560-8
ISSN	2044-5385 ; 2044-5385
ISSN (online)	2044-5385
ISSN	2044-5385
DOI	10.1038/s41408-022-00716-3
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Article ; Online: Combination therapy targeting Erk1/2 and CDK4/6i in relapsed refractory multiple myeloma.

Adamia, Sophia / Bhatt, Shruti / Wen, Kenneth / Chyra, Zuzana / Fell, Geoffrey G / Tai, Yu-Tzu / Pioso, Marisa S / Abiatari, Ivane / Letai, Anthony / Dorfman, David M / Hideshima, Teru / Anderson, Kenneth C

Leukemia

2022 Volume 36, Issue 4, Page(s) 1088–1101

Abstract: Oncogenic activated RAS mutations have been detected in 50% of de novo and 70% of relapsed multiple myeloma (MM) patients. Translocation t(11;14) involving IgH/CCDN1 and overexpression of cyclin-Ds are early events in MM pathogenesis, enhancing ... ...

Abstract	Oncogenic activated RAS mutations have been detected in 50% of de novo and 70% of relapsed multiple myeloma (MM) patients. Translocation t(11;14) involving IgH/CCDN1 and overexpression of cyclin-Ds are early events in MM pathogenesis, enhancing uncontrolled MM cell growth. We hypothesized that targeting both RAS/MAPK pathway molecules including Erk1/2 along with cyclin-Ds enhances MM cytotoxicity and minimizes side effects. Recent studies have demonstrated the high potency of Erk1/2 and CDK4/6 inhibitors in metastatic relapsed cancers, and here we tested anti-MM effects of the Erk1/2 + CDK4/6 inhibitor combination. Our studies showed strong synergistic (IC < 0.5) cytotoxicity of Erk1/2i + CDK4/6i in MM-cells. Erk1/2i + CDK4/6i treatment in a dose-dependent manner arrested MM-cells in the G0/G1 phase and activated mitochondrial apoptotic signaling. Our studies showed that Erk1/2i + CDK4/6i treatment-induced inhibition of key target molecules in Erk1/2 and CDK4/6 signaling, such as c-myc, p-RSK, p-S6, p-RB, and E2F1, suggesting on-target activity of these inhibitors. We identified Erk1/2i + CDK4/6i treatment associated five-gene signature which includes SNRPB and SLC25A5; these genes are involved in RNA processing and mitochondrial metabolism, respectively. Overall, our studies provide the preclinical framework for Erk1/2i + CDK4/6i combination clinical trials to target Ras+CDK pathways to improve patient outcome in MM.
MeSH term(s)	Breast Neoplasms/drug therapy ; Cyclin-Dependent Kinase 4 ; Cyclin-Dependent Kinase 6 ; Female ; Humans ; Multiple Myeloma/drug therapy ; Neoplasm Recurrence, Local/drug therapy ; Protein Kinase Inhibitors/therapeutic use
Chemical Substances	Protein Kinase Inhibitors ; CDK4 protein, human (EC 2.7.11.22) ; Cyclin-Dependent Kinase 4 (EC 2.7.11.22) ; Cyclin-Dependent Kinase 6 (EC 2.7.11.22)
Language	English
Publishing date	2022-01-27
Publishing country	England
Document type	Journal Article
ZDB-ID	807030-1
ISSN	1476-5551 ; 0887-6924
ISSN (online)	1476-5551
ISSN	0887-6924
DOI	10.1038/s41375-021-01475-z
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Zs.A 2295: Show issues

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Je nach Verfügbarkeit (siehe Angabe bei Bestand)
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ab Jg. 2022: Lesesaal (EG)

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Article ; Online: Author Correction: Combination therapy targeting Erk1/2 and CDK4/6i in relapsed refractory multiple myeloma.

Adamia, Sophia / Bhatt, Shruti / Wen, Kenneth / Chyra, Zuzana / Fell, Geoffrey G / Tai, Yu-Tzu / Pioso, Marissa S / Abiatari, Ivane / Letai, Anthony / Dorfman, David M / Hideshima, Teru / Anderson, Kenneth C

Leukemia

2022 Volume 36, Issue 6, Page(s) 1700

Language	English
Publishing date	2022-05-05
Publishing country	England
Document type	Published Erratum
ZDB-ID	807030-1
ISSN	1476-5551 ; 0887-6924
ISSN (online)	1476-5551
ISSN	0887-6924
DOI	10.1038/s41375-022-01588-z
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Zs.A 2295: Show issues

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Je nach Verfügbarkeit (siehe Angabe bei Bestand)
bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
Jg. 1995 - 2021: Lesesall (2.OG)
ab Jg. 2022: Lesesaal (EG)

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Article ; Online: The immunomodulatory drugs lenalidomide and pomalidomide enhance the potency of AMG 701 in multiple myeloma preclinical models.

Cho, Shih-Feng / Lin, Liang / Xing, Lijie / Li, Yuyin / Wen, Kenneth / Yu, Tengteng / Hsieh, Phillip A / Munshi, Nikhil / Wahl, Joachim / Matthes, Katja / Friedrich, Matthias / Arvedson, Tara / Anderson, Kenneth C / Tai, Yu-Tzu

Blood advances

2021 Volume 4, Issue 17, Page(s) 4195–4207

Abstract: We investigated here the novel immunomodulation and anti-multiple myeloma (MM) function of T cells engaged by the bispecific T-cell engager molecule AMG 701, and further examined the impact of AMG 701 in combination with immunomodulatory drugs (IMiDs; ... ...

Abstract	We investigated here the novel immunomodulation and anti-multiple myeloma (MM) function of T cells engaged by the bispecific T-cell engager molecule AMG 701, and further examined the impact of AMG 701 in combination with immunomodulatory drugs (IMiDs; lenalidomide and pomalidomide). AMG 701 potently induced T-cell-dependent cellular cytotoxicity (TDCC) against MM cells expressing B-cell maturation antigen, including autologous cells from patients with relapsed and refractory MM (RRMM) (half maximal effective concentration, <46.6 pM). Besides inducing T-cell proliferation and cytolytic activity, AMG 701 also promoted differentiation of patient T cells to central memory, effector memory, and stem cell-like memory (scm) phenotypes, more so in CD8 vs CD4 T subsets, resulting in increased CD8/CD4 ratios in 7-day ex vivo cocultures. IMiDs and AMG 701 synergistically induced TDCC against MM cell lines and autologous RRMM patient cells, even in the presence of immunosuppressive bone marrow stromal cells or osteoclasts. IMiDs further upregulated AMG 701-induced patient T-cell differentiation toward memory phenotypes, associated with increased CD8/CD4 ratios, increased Tscm, and decreased interleukin 10-positive T and T regulatory cells (CD25highFOXP3high), which may downregulate T effector cells. Importantly, the combination of AMG 701 with lenalidomide induced sustained inhibition of MM cell growth in SCID mice reconstituted with human T cells; tumor regrowth was eventually observed in cohorts treated with either agent alone (P < .001). These results strongly support AMG 701 clinical studies as monotherapy in patients with RRMM (NCT03287908) and the combination with IMiDs to improve patient outcomes in MM.
MeSH term(s)	Animals ; Humans ; Immunomodulation ; Lenalidomide ; Mice ; Mice, SCID ; Multiple Myeloma/drug therapy ; Pharmaceutical Preparations ; Thalidomide/analogs & derivatives
Chemical Substances	Pharmaceutical Preparations ; Thalidomide (4Z8R6ORS6L) ; pomalidomide (D2UX06XLB5) ; Lenalidomide (F0P408N6V4)
Language	English
Publishing date	2021-05-11
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2915908-8
ISSN	2473-9537 ; 2473-9529
ISSN (online)	2473-9537
ISSN	2473-9529
DOI	10.1182/bloodadvances.2020002524
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Zs.A 7153: Show issues

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Article ; Online: Development of a Covalent Inhibitor of c-Jun N-Terminal Protein Kinase (JNK) 2/3 with Selectivity over JNK1.

Journal of medicinal chemistry

2023 Volume 66, Issue 5, Page(s) 3356–3371

Abstract: The c-Jun N-terminal kinases (JNKs) are members of the mitogen-activated protein kinase (MAPK) family, which includes JNK1-JNK3. Interestingly, JNK1 and JNK2 show opposing functions, with JNK2 activity favoring cell survival and JNK1 stimulating ... ...

Abstract	The c-Jun N-terminal kinases (JNKs) are members of the mitogen-activated protein kinase (MAPK) family, which includes JNK1-JNK3. Interestingly, JNK1 and JNK2 show opposing functions, with JNK2 activity favoring cell survival and JNK1 stimulating apoptosis. Isoform-selective small molecule inhibitors of JNK1 or JNK2 would be useful as pharmacological probes but have been difficult to develop due to the similarity of their ATP binding pockets. Here, we describe the discovery of a covalent inhibitor YL5084, the first such inhibitor that displays selectivity for JNK2 over JNK1. We demonstrated that YL5084 forms a covalent bond with Cys116 of JNK2, exhibits a 20-fold higher
MeSH term(s)	JNK Mitogen-Activated Protein Kinases ; Mitogen-Activated Protein Kinase 8/metabolism ; Mitogen-Activated Protein Kinase 9/metabolism ; Mitogen-Activated Protein Kinases/metabolism ; Phosphorylation
Chemical Substances	JNK Mitogen-Activated Protein Kinases (EC 2.7.11.24) ; Mitogen-Activated Protein Kinase 8 (EC 2.7.11.24) ; Mitogen-Activated Protein Kinase 9 (EC 2.7.1.24) ; Mitogen-Activated Protein Kinases (EC 2.7.11.24) ; YL5084
Language	English
Publishing date	2023-02-24
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	218133-2
ISSN	1520-4804 ; 0022-2623
ISSN (online)	1520-4804
ISSN	0022-2623
DOI	10.1021/acs.jmedchem.2c01834
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Zs.B 151: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular ab Jg. 2022: Lesesaal (EG)
Zs.MB 1: Show issues

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Article ; Online: Targeting LAG3/GAL-3 to overcome immunosuppression and enhance anti-tumor immune responses in multiple myeloma.

Bae, Jooeun / Accardi, Fabrizio / Hideshima, Teru / Tai, Yu-Tzu / Prabhala, Rao / Shambley, Aaron / Wen, Kenneth / Rowell, Sean / Richardson, Paul G / Munshi, Nikhil C / Anderson, Kenneth C

Leukemia

2021 Volume 36, Issue 1, Page(s) 138–154

Abstract: Immune profiling in patients with monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), and multiple myeloma (MM) provides the framework for developing novel immunotherapeutic strategies. Here, we demonstrate ... ...

Abstract	Immune profiling in patients with monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), and multiple myeloma (MM) provides the framework for developing novel immunotherapeutic strategies. Here, we demonstrate decreased CD4
MeSH term(s)	Antigens, CD/chemistry ; Apoptosis ; Blood Proteins/antagonists & inhibitors ; Case-Control Studies ; Cell Proliferation ; Follow-Up Studies ; Galectins/antagonists & inhibitors ; Humans ; Immunosuppression Therapy/methods ; Leukocytes, Mononuclear/immunology ; Leukocytes, Mononuclear/metabolism ; Leukocytes, Mononuclear/pathology ; Lymphocyte Activation ; Monoclonal Gammopathy of Undetermined Significance/immunology ; Monoclonal Gammopathy of Undetermined Significance/metabolism ; Monoclonal Gammopathy of Undetermined Significance/pathology ; Monoclonal Gammopathy of Undetermined Significance/therapy ; Multiple Myeloma/immunology ; Multiple Myeloma/metabolism ; Multiple Myeloma/pathology ; Multiple Myeloma/therapy ; Prognosis ; T-Lymphocytes, Cytotoxic/immunology ; Tumor Cells, Cultured ; Lymphocyte Activation Gene 3 Protein
Chemical Substances	Antigens, CD ; Blood Proteins ; Galectins ; LGALS3 protein, human ; Lymphocyte Activation Gene 3 Protein ; Lag3 protein, human
Language	English
Publishing date	2021-07-21
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	807030-1
ISSN	1476-5551 ; 0887-6924
ISSN (online)	1476-5551
ISSN	0887-6924
DOI	10.1038/s41375-021-01301-6
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Zs.A 2295: Show issues

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ab Jg. 2022: Lesesaal (EG)

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Article ; Online: Loss of GABARAP mediates resistance to immunogenic chemotherapy in multiple myeloma.

Gulla, Annamaria / Morelli, Eugenio / Johnstone, Megan / Turi, Marcello / Samur, Mehmet K / Botta, Cirino / Cifric, Selma / Folino, Pietro / Vinaixa, Delaney / Barello, Francesca / Clericuzio, Cole / Favasuli, Vanessa Katia / Maisano, Domenico / Talluri, Srikanth / Prabhala, Rao H / Bianchi, Giada / Fulciniti, Mariateresa / Wen, Kenneth / Kurata, Keiji /

Liu, Jiye / Penailillo, Johany / Bragoni, Alberto / Sapino, Anna / Richardson, Paul G / Chauhan, Dharminder / Carrasco, Ruben D / Hideshima, Teru / Munshi, Nikhil C / Anderson, Kenneth C

Blood

2024

Abstract: Immunogenic cell death (ICD) is a form of cell death by which cancer treatments can induce a clinically relevant anti-tumor immune response in a broad range of cancers. In multiple myeloma (MM), the proteasome inhibitor bortezomib is an ICD inducer and ... ...

Abstract	Immunogenic cell death (ICD) is a form of cell death by which cancer treatments can induce a clinically relevant anti-tumor immune response in a broad range of cancers. In multiple myeloma (MM), the proteasome inhibitor bortezomib is an ICD inducer and creates durable therapeutic responses in patients. However, eventual relapse and resistance to bortezomib appear inevitable. Here, by integrating patient transcriptomic data with an analysis of calreticulin (CRT) protein interactors, we found that GABARAP is a key player whose loss prevented tumor cell death from being perceived as immunogenic after bortezomib treatment. GABARAP is located on chromosome 17p, which is commonly deleted in high-risk MM patients. GABARAP deletion impaired the exposure of the eat-me signal CRT on the surface of dying MM cells in vitro and in vivo, thus reducing tumor cell phagocytosis by dendritic cells and the subsequent anti-tumor T cell response. Low GABARAP was independently associated with shorter MM patient survival and reduced tumor immune infiltration. Mechanistically, we found that GABARAP deletion blocked ICD signaling by decreasing autophagy and altering Golgi apparatus morphology, with consequent defects in the downstream vesicular transport of CRT. Conversely, upregulating autophagy using rapamycin restored Golgi morphology, CRT exposure and ICD signaling in GABARAPKO cells undergoing bortezomib treatment. Therefore, coupling an ICD inducer, like bortezomib, with an autophagy inducer, like rapamycin, may improve patient outcomes in MM, where low GABARAP in the form of del(17p) is common and leads to worse outcomes.
Language	English
Publishing date	2024-03-29
Publishing country	United States
Document type	Journal Article
ZDB-ID	80069-7
ISSN	1528-0020 ; 0006-4971
ISSN (online)	1528-0020
ISSN	0006-4971
DOI	10.1182/blood.2023022777
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