MAPK pathway activation leads to Bim loss and histone deacetylase inhibitor resistance: rationale to combine romidepsin with an MEK inhibitor

Chakraborty, Arup; Robey, Robert W.; Luchenko, Victoria; Zhan, Zhirong; Piekarz, Richard; Gillet, Jean‐Pierre; Kossenkov, Andrew V.; Wilkerson, Julia; Showe, Louise C.; Gottesman, Michael M.; Collie, Nathan L.; Bates, Susan E.

doi:10.1182/blood-2012-08-449140

Cited by 77 publications

(84 citation statements)

References 37 publications

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“…11 We recently demonstrated that upregulation of the mitogen-activated protein kinase pathway led to Bim degradation and resistance to histone deacetylase inhibitors in a model of cutaneous T-cell lymphoma. 12 Combination of an HDI with inhibitors of signaling pathways leads to increased apopotosis in several cell line models. [13][14][15] Various reports have shown that HDIs mediate apoptosis through both the intrinsic and extrinsic pathways.…”

Section: Introductionmentioning

confidence: 99%

Loss of the proteins Bak and Bax prevents apoptosis mediated by histone deacetylase inhibitors

Ieranò¹,

Chakraborty²,

Nicolae³

et al. 2013

Cell Cycle

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Section: Introductionmentioning

confidence: 99%

Loss of the proteins Bak and Bax prevents apoptosis mediated by histone deacetylase inhibitors

Ieranò¹,

Chakraborty²,

Nicolae³

et al. 2013

Cell Cycle

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“…Romidepsin induced p21 in all 4 cell lines while belinostat induced p21 in THJ-21T and vorinostat induced p21 in THJ-11T and THJ-21T. Since BIM degradation can be regulated by Erk signaling (Akiyama, et al 2009; Chakraborty, et al 2013), p-Erk and p-Akt (data not shown) expression was examined and no consistent change in expression was found within or across the four ATC cell lines examined (Figure 1C). …”

Section: Resultsmentioning

confidence: 94%

RhoB upregulation leads to either apoptosis or cytostasis through differential target selection

Marlow¹,

Bok²,

Smallridge³

et al. 2015

Endocrine-Related Cancer

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Anaplastic thyroid carcinoma is a highly aggressive undifferentiated carcinoma with a mortality rate near 100% that is due to an assortment of genomic abnormalities that impedes the success of therapeutic options. Our laboratory has previously identified that RhoB upregulation serves as a novel molecular therapeutic target and agents upregulating RhoB combined with paclitaxel lead to antitumor synergy. Knowing that histone deacetylase (HDAC) 1 transcriptionally suppresses RhoB, we sought to extend our findings to other HDACs and to identify the HDAC inhibitor (HDACi) that optimally synergize with paclitaxel. Here we identify HDAC6 as a newly discovered RhoB repressor. By using isoform selective HDAC inhibitors (HDACi) and shRNAs, we show that RhoB has divergent downstream signaling partners, which are dependent on the HDAC isoform that is inhibited. When RhoB upregulates only p21(cyclin kinase inhibitor) using a class I HDACi (romidepsin), cells undergo cytostasis. When RhoB upregulates BIMEL using class II/(I) HDACi (belinostat or vorinostat), apoptosis occurs. Combinatorial synergy with paclitaxel is dependent upon RhoB and BIMEL while upregulation of RhoB and only p21 blocks synergy. This bifurcated regulation of the cell cycle by RhoB is novel and silencing either p21 or BIMEL turns the previously silenced pathway on, leading to phenotypic reversal. This study intimates that the combination of belinostat/vorinostat with paclitaxel may prove to be an effective therapeutic strategy via the novel observation that class II/(I) HDACi antagonize HDAC6-mediated suppression of RhoB and subsequent BIMEL, thereby promoting antitumor synergy. These overall observations may provide a mechanistic understanding of optimal therapeutic response.

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“…The loss of the pro-apoptotic protein Bim and the abnormal activation of the mitogen-activated protein kinase pathway could be a fundamental resistance mechanism to HDACi compared with parental cells (19). Chakraborty et al (20) have therefore studied in vitro the combination of romidepsin, which is another HDACi, with an anti-mitogen-activated kinase (MEK) for the treatment of CTCL. In vitro, the anti-MEK combined with romidepsin leads specifically to apoptosis and could then be correlated with the restoration of Bim.…”

Section: Discussionmentioning

confidence: 99%

Vorinostat for Refractory or Relapsing Epidermotropic T-cell Lymphoma: A Retrospective Cohort Study of 15 Patients

Kogge¹,

Volteau²,

Saint‐Jean³

et al. 2015

Acta Derm Venerol

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Since the approval of vorinostat for the treatment of refractory cutaneous epidermotropic T-cell lymphoma (CTCL) in 2006, very little data about this treatment have been published. The aim of this retrospective study was to assess the efficacy and safety of vorinostat in patients with CTCL treated between 2007 and 2013 in our department. Fifteen patients (median age 64 years) were included: 9 with Sézary syndrome and 6 with mycosis fungoides. They were all in progression and the median number of systemic treatments previously administered was 3 (range 1-7). With vorinostat treatment, the best response was partial remission in 5 patients (33%) and stabilization in 4 patients (27%). Six patients experienced disease progression. The mean time to response and response duration were 70 (range 31-140) and 300 days (range 157-663), respectively. The most frequent adverse events were asthenia, weight loss, nausea and anaemia. Vorinostat could be a therapeutic alternative for CTCL after treatment failure.

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MAPK pathway activation leads to Bim loss and histone deacetylase inhibitor resistance: rationale to combine romidepsin with an MEK inhibitor

Abstract: Key Points MAPK pathway activation and Bim loss may represent a fundamental mechanism of resistance to histone deacetylase inhibitors. Combination of romidepsin with an MEK inhibitor may lead to greater responses in cancers in which the MAPK pathway is active.

Cited by 77 publications

References 37 publications

Loss of the proteins Bak and Bax prevents apoptosis mediated by histone deacetylase inhibitors

Loss of the proteins Bak and Bax prevents apoptosis mediated by histone deacetylase inhibitors

RhoB upregulation leads to either apoptosis or cytostasis through differential target selection

Vorinostat for Refractory or Relapsing Epidermotropic T-cell Lymphoma: A Retrospective Cohort Study of 15 Patients

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