A Bim-targeting strategy overcomes adaptive bortezomib resistance in myeloma through a novel link between autophagy and apoptosis

Chen, Shuang; Zhang, Yu; Zhou, Liang; Leng, Yun; Lin, Hui‐Yi; Kmieciak, Maciej; Pei, Xin Yan; Jones, Richard J.; Orłowski, Robert Z.; Dai, Yun; Grant, Steven

doi:10.1182/blood-2014-03-564534

Cited by 86 publications

(80 citation statements)

References 67 publications

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“…Combined treatment with panobinostat and FK506 enhanced cleavage of caspase-7 and -3 while increasing the BCL2-family protein BimS expression compared with panobinostat alone (Figure 4A). The previous study showed that Bim gene KO mouse embryo fibroblasts displayed diminished HDAC inhibitor-mediated apoptosis (36). These results suggest the importance of enhanced expression of Bim in HDAC inhibitor-mediated apoptosis and the possibility of blocking the effect of combined treatment with panobinostat and FK506 by shRNA Bim knockdown.…”

Section: The Effects Of Calcineurin Inhibition On Apoptosis and Prolimentioning

confidence: 86%

Histone deacetylase inhibitor panobinostat induces calcineurin degradation in multiple myeloma

et al. 2016

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Section: The Effects Of Calcineurin Inhibition On Apoptosis and Prolimentioning

confidence: 86%

Histone deacetylase inhibitor panobinostat induces calcineurin degradation in multiple myeloma

et al. 2016

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“…MM cell lines acquired drug resistance were generated as described earlier 28. Cells were cultured in a humidified incubator at 37°C and 5% CO 2 .…”

Section: Methodsmentioning

confidence: 99%

ARNT/HIF‐1β links high‐risk 1q21 gain and microenvironmental hypoxia to drug resistance and poor prognosis in multiple myeloma

Yang

Liu

et al. 2018

Cancer Medicine

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Abstract1q21 gain is a common cytogenetic abnormality featuring high‐risk multiple myeloma (HRMM). However, the molecular mechanism underlying the adverse prognostic effect of 1q21 gain remains largely unclear. Here, we report that ARNT/HIF‐1β, a 1q21 gene, is highly expressed in HRMM and induced by microenvironmental hypoxia, which confers drug resistance and correlates with inferior outcome. Analysis of the gene expression profile database revealed that ARNT expression was upregulated in MM and increased with disease progression or in HRMM subtypes (particularly 1q21 gain), while correlated to shorter overall survival. In a cohort of 40 MM patients, qPCR further validated that ARNT expression was higher in MM patients than normal donors. MM cells carrying 1q21 gain or acquired drug resistance displayed a robust increase in HIF‐1β protein level. Hypoxia induced HIF‐1β expression via a NF‐κB‐dependent process. Notably, HIF‐1β overexpression impaired bortezomib sensitivity, whereas shRNA knockdown of ARNT reversed hypoxia‐mediated drug resistance. Together, these findings suggest that ARNT/HIF‐1β might represent a novel biomarker for risk stratification and prognosis of HRMM patients, as well as a potential therapeutic target for overcoming 1q21 gain‐ or microenvironment‐mediated and acquired drug resistance in MM.

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“…For example, Bim, known to be a key determinant of neoplastic cell sensitivity to various targeted agents (e.g. kinase inhibitors), has also been shown to be a significant factor in resistance of multiple myeloma cells to proteasome inhibitors [25] and of myeloid leukemia cells to histone deacetylase inhibitors [26]. Furthermore, activation of the multidomain pro-apoptotic proteins Bak and Bax play key roles in cell death regulation.…”

Section: Bcl-2 Family Proteins and Malignant Cell Survival And Resistmentioning

confidence: 99%

“…Among their numerous actions, HDACIs have been shown to upregulate expression of Bim through an E2F-dependent process [68]. Notably, HDACIs, when combined with BH3-mimetics such as ABT-737, effectively trigger apoptosis in multiple myeloma cells exhibiting either intrinsic or acquired resistance to bortezomib [25] through a process depending, at least in part, upon Bim upregulation. Whether similar effects occur in multiple myeloma cells exposed to venetoclax remains to be determined.…”

Section: Histone Deacetylase Inhibitors (Hdacis)mentioning

confidence: 99%

Rational combination strategies to enhance venetoclax activity and overcome resistance in hematologic malignancies

Grant

2017

Leukemia & Lymphoma

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Venetoclax (ABT-199) is a Bcl-2-specific BH3-mimetic that has shown significant promise in certain subtypes of CLL as well as in several other hematologic malignancies. As in the case of essentially all targeted agents, intrinsic or acquired resistance to this agent generally occurs, prompting the search for new strategies capable of circumventing this problem. A logical approach to this challenge involves rational combination strategies designed to disable preexisting or induced compensatory survival pathways. Many of these strategies involve downregulation of Mcl-1, a pro-survival Bcl-2 family member that is not targeted by venetoclax, and which often confers resistance to this agent. Given encouraging clinical results involving venetoclax in both lymphoid and myeloid malignancies, it is likely that such combination approaches will be incorporated into the therapeutic armamentarium for multiple hematologic malignancies in the near future.

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A Bim-targeting strategy overcomes adaptive bortezomib resistance in myeloma through a novel link between autophagy and apoptosis

Abstract: Key Points• Loss of Bim contributes to adaptive rather than intrinsic bortezomib resistance in multiple myeloma.• A Bim-targeting strategy combining an HDACI with a BH3 mimetic overcomes such resistance through a new link between autophagy and apoptosis.

Cited by 86 publications

References 67 publications

Histone deacetylase inhibitor panobinostat induces calcineurin degradation in multiple myeloma

Histone deacetylase inhibitor panobinostat induces calcineurin degradation in multiple myeloma

ARNT/HIF‐1β links high‐risk 1q21 gain and microenvironmental hypoxia to drug resistance and poor prognosis in multiple myeloma

Rational combination strategies to enhance venetoclax activity and overcome resistance in hematologic malignancies

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