TG02 inhibits proteasome inhibitor–induced HSF1 serine 326 phosphorylation and heat shock response in multiple myeloma

Shah, Shardule P.; Nooka, Ajay K.; Lonial, Sagar; Boise, Lawrence H.

doi:10.1182/bloodadvances.2017006122

Cited by 3 publications

(2 citation statements)

References 15 publications

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“…Furthermore, bortezomib treatment is beneficial in pediatric acute myeloid leukemia patients with low HSF1 pSer326 as compared to those with high levels of HSF1 pSer326 53 . In order to tackle resistance development, specific multi-kinase inhibitors are under development to overcome resistance due to proteasome inhibitor induced HSF1 pSer326 and may serve as a novel means to treat cancer relapse 54 .…”

Section: Post Translational Modifications (Ptms)mentioning

confidence: 99%

Targeting HSF1 for cancer treatment: mechanisms and inhibitor development

Chin¹,

Gumilar²,

Li³

et al. 2023

Theranostics

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Section: Post Translational Modifications (Ptms)mentioning

confidence: 99%

Targeting HSF1 for cancer treatment: mechanisms and inhibitor development

Chin¹,

Gumilar²,

Li³

et al. 2023

Theranostics

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“…The putative resistance mechanism remains incompletely understood, with several potential mechanisms suggested. Among them, the activation of the heat shock response stands out as one of the most prominent cytoprotective mechanisms ( 1 ). Mutations and abnormal expression of components within the ubiquitin-proteasome system are additional factors that can result in resistance to PIs ( ( 2 – 4 ).…”

Section: Introductionmentioning

confidence: 99%

Co-operation of MCL-1 and BCL-XL anti-apoptotic proteins in stromal protection of MM cells from carfilzomib mediated cytotoxicity

Galas-Filipowicz,

Chavda,

Gong

et al. 2024

Front. Oncol.

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IntroductionBCL-2 family proteins are important for tumour cell survival and drug resistance in multiple myeloma (MM). Although proteasome inhibitors are effective anti-myeloma drugs, some patients are resistant and almost all eventually relapse. We examined the function of BCL-2 family proteins in stromal-mediated resistance to carfilzomib-induced cytotoxicity in MM cells.MethodsCo-cultures employing HS5 stromal cells were used to model the interaction with stroma. MM cells were exposed to CFZ in a 1-hour pulse method. The expression of BCL-2 family proteins was assessed by flow cytometry and WB. Pro-survival proteins: MCL-1, BCL-2 and BCL-XL were inhibited using S63845, ABT-199 and A-1331852 respectively. Changes in BIM binding partners were examined by immunoprecipitation and WB.ResultsCFZ induced dose-dependent cell death of MM cells, primarily mediated by apoptosis. Culture of MM cells on HS-5 stromal cells resulted in reduced cytotoxicity to CFZ in a cell contact-dependent manner, upregulated expression of MCL-1 and increased dependency on BCL-XL. Inhibiting BCL-XL or MCL-1 with BH-3 mimetics abrogated stromal-mediated protection only at high doses, which may not be achievable in vivo. However, combining BH-3 mimetics at sub-therapeutic doses, which alone were without effect, significantly enhanced CFZ-mediated cytotoxicity even in the presence of stroma. Furthermore, MCL-1 inhibition led to enhanced binding between BCL-XL and BIM, while blocking BCL-XL increased MCL-1/BIM complex formation, indicating the cooperative role of these proteins.ConclusionStromal interactions alter the dependence on BCL-2 family members, providing a rationale for dual inhibition to abrogate the protective effect of stroma and restore sensitivity to CFZ.

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Heat shock factor 1 (HSF1-pSer326) predicts response to bortezomib-containing chemotherapy in pediatric AML: a COG report

Hoff

Dijk

Qiu³

et al. 2021

Blood

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Bortezomib (BTZ) was recently evaluated in a randomized Phase 3 clinical trial which compared standard chemotherapy (cytarabine, daunorubicin, etoposide; ADE) to standard therapy with BTZ (ADEB) for de novo pediatric acute myeloid leukemia. While the study concluded that BTZ did not improve outcome overall, we examined patient subgroups benefitting from BTZ-containing chemotherapy using proteomic analyses. The proteasome inhibitor BTZ disrupts protein homeostasis and activates cytoprotective heat shock responses. We measured total heat shock factor 1 (HSF1) and phosphorylated HSF1 (HSF1-pSer326) in leukemic cells from 483 pediatric patients using Reverse Phase Protein Arrays. HSF1-pSer326 phosphorylation was significantly lower in pediatric AML compared to CD34+ non-malignant cells. We identified a strong correlation between HSF1-pSer326 expression and BTZ sensitivity. BTZ significantly improved outcome of patients with low-HSF1-pSer326 with a 5-year event-free survival of 44% (ADE) vs. 67% for low-HSF1-pSer326 treated with ADEB (P=0.019). To determine the effect of HSF1 expression on BTZ potency in vitro, cell viability with HSF1 gene variants that mimicked phosphorylated (S326A) and non-phosphorylated (S326E) HSF1-pSer326 were examined. Those with increased HSF1 phosphorylation showed clear resistance to BTZ vs. those with wild type or reduced HSF1-phosphorylation. We hypothesize that HSF1-pSer326 expression could identify patients that benefit from BTZ-containing chemotherapy.

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TG02 inhibits proteasome inhibitor–induced HSF1 serine 326 phosphorylation and heat shock response in multiple myeloma

Abstract: Key Points Proteasome inhibition activates multiple kinases in myeloma cells resulting in the phosphorylation of p53, HSP27, c-JUN, and HSF1. TG02 inhibits proteasome inhibitor (PI)–induced HSF1 pS326, representing a novel mechanism for a TG02 and PI combination.

Cited by 3 publications

References 15 publications

Targeting HSF1 for cancer treatment: mechanisms and inhibitor development

Targeting HSF1 for cancer treatment: mechanisms and inhibitor development

Co-operation of MCL-1 and BCL-XL anti-apoptotic proteins in stromal protection of MM cells from carfilzomib mediated cytotoxicity

Heat shock factor 1 (HSF1-pSer326) predicts response to bortezomib-containing chemotherapy in pediatric AML: a COG report

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