Synergistic efficacy of combined EGFR and HDAC inhibitors overcomes tolerance to EGFR monotherapy in salivary mucoepidermoid carcinoma

Parag-Sharma, Kshitij; Tasoulas, Jason; Musicant, Adele M.; Nascimento-Filho, Carlos H. V.; Zhu, Zhen-Gang; Twomey, Chloe; Liu, Pengda; Castilho, Rogerio M.; Amelio, Antonio L.

doi:10.1016/j.oraloncology.2020.105166

Cited by 15 publications

(19 citation statements)

References 49 publications

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“…Currently, several HDAC inhibitors are in clinical use as anticancer agents. In salivary gland cancer, HDAC inhibitors combined with epithelial growth factor receptor (EGFR) inhibitors exert synergistic and potent cytotoxic effects [ 30 ]. We previously reported that the HDAC inhibitors TSA and quisinostat suppressed malignancy via changes of the expression of TJ proteins in lung adenocarcinoma, and that TSA also suppressed the proliferation, migration, and invasion of HNSCC cells via p63-mediated tight junction molecules and p21-mediated growth arrest [ 62 , 63 ].…”

Section: Discussionmentioning

confidence: 99%

“…HDAC inhibitors are epigenetic regulators that relax chromatin structures through increased acetylation of histones and, as a result, induce cell cycle arrest, differentiation, and the apoptosis of malignant cells [ 27 , 28 , 29 ]. Furthermore, HDAC inhibitors, when combined with known therapies, inhibit resistance to antitumor drugs [ 30 ]. Therefore, HDAC inhibitors demonstrate the potential to be a new major treatment that exhibits antitumor activities.…”

Section: Introductionmentioning

confidence: 99%

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Inhibition of HDAC and Signal Transduction Pathways Induces Tight Junctions and Promotes Differentiation in p63-Positive Salivary Duct Adenocarcinoma

Nakano

Ohwada

Shindo

et al. 2022

Cancers

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Background: The p53 family p63 is essential for the proliferation and differentiation of various epithelial basal cells. It is overexpressed in several cancers, including salivary gland neoplasia. Histone deacetylases (HDACs) are thought to play a crucial role in carcinogenesis, and HDAC inhibitors downregulate p63 expression in cancers. Methods: In the present study, to investigate the roles and regulation of p63 in salivary duct adenocarcinoma (SDC), human SDC cell line A253 was transfected with siRNA-p63 or treated with the HDAC inhibitors trichostatin A (TSA) and quisinostat (JNJ-26481585). Results: In a DNA array, the knockdown of p63 markedly induced mRNAs of the tight junction (TJ) proteins cingulin (CGN) and zonula occuludin-3 (ZO-3). The knockdown of p63 resulted in the recruitment of the TJ proteins, the angulin-1/lipolysis-stimulated lipoprotein receptor (LSR), occludin (OCLN), CGN, and ZO-3 at the membranes, preventing cell proliferation, and leading to increased cell metabolism. Treatment with HDAC inhibitors downregulated the expression of p63, induced TJ structures, recruited the TJ proteins, increased the epithelial barrier function, and prevented cell proliferation and migration. Conclusions: p63 is not only a diagnostic marker of salivary gland neoplasia, but it also promotes the malignancy. Inhibition of HDAC and signal transduction pathways is, therefore, useful in therapy for p63-positive SDC cells.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Inhibition of HDAC and Signal Transduction Pathways Induces Tight Junctions and Promotes Differentiation in p63-Positive Salivary Duct Adenocarcinoma

Nakano

Ohwada

Shindo

et al. 2022

Cancers

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“…Unfortunately, therapeutic strategies to manage disseminated diseases and metastatic tumors are lacking, and new strategies are needed. 3,18 Although several chemotherapy protocols have been studied in the management of MEC, a generally low level of response is observed. [19][20][21] Therefore, in this pioneering study, we investigate the effects of Cephaeline on MEC cell line behavior.…”

Section: Discussionmentioning

confidence: 99%

“…Management of MEC follows similar protocols in the use for other malignancies from the salivary glands. Unfortunately, therapeutic strategies to manage disseminated diseases and metastatic tumors are lacking, and new strategies are needed 3,18 . Although several chemotherapy protocols have been studied in the management of MEC, a generally low level of response is observed 19–21 .…”

Section: Discussionmentioning

confidence: 99%

Cephaeline is an inductor of histone H3 acetylation and inhibitor of mucoepidermoid carcinoma cancer stem cells

Silva

Borgato

Wagner

et al. 2021

J Oral Pathology Medicine

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“…In contrast, reversible EGFR inhibitors such as Erlotinib, Lapatinib, and Gefitinib compete with ATP for the ATP binding pocket on EGFR without establishing any covalent interaction [ 59 , 60 ]. In a recent study, Erlotinib and the HDAC inhibitor SAHA displayed synergistic efficacy against mucoepidermoid carcinoma [ 176 ]. A similar combinatory approach with EHMT inhibitors can be considered for cancers with aberrant EGFR signaling and EHMT expression.…”

Section: Targeting Regulators and Ehmt Interactors In Cancermentioning

confidence: 99%

Potential Therapeutics Targeting Upstream Regulators and Interactors of EHMT1/2

Ang

Gupta

Surana

et al. 2022

Cancers

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Euchromatin histone lysine methyltransferases (EHMTs) are epigenetic regulators responsible for silencing gene transcription by catalyzing H3K9 dimethylation. Dysregulation of EHMT1/2 has been reported in multiple cancers and is associated with poor clinical outcomes. Although substantial insights have been gleaned into the downstream targets and pathways regulated by EHMT1/2, few studies have uncovered mechanisms responsible for their dysregulated expression. Moreover, EHMT1/2 interacting partners, which can influence their function and, therefore, the expression of target genes, have not been extensively explored. As none of the currently available EHMT inhibitors have made it past clinical trials, understanding upstream regulators and EHMT protein complexes may provide unique insights into novel therapeutic avenues in EHMT-overexpressing cancers. Here, we review our current understanding of the regulators and interacting partners of EHMTs. We also discuss available therapeutic drugs that target the upstream regulators and binding partners of EHMTs and could potentially modulate EHMT function in cancer progression.

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Synergistic efficacy of combined EGFR and HDAC inhibitors overcomes tolerance to EGFR monotherapy in salivary mucoepidermoid carcinoma

Cited by 15 publications

References 49 publications

Inhibition of HDAC and Signal Transduction Pathways Induces Tight Junctions and Promotes Differentiation in p63-Positive Salivary Duct Adenocarcinoma

Inhibition of HDAC and Signal Transduction Pathways Induces Tight Junctions and Promotes Differentiation in p63-Positive Salivary Duct Adenocarcinoma

Cephaeline is an inductor of histone H3 acetylation and inhibitor of mucoepidermoid carcinoma cancer stem cells

Potential Therapeutics Targeting Upstream Regulators and Interactors of EHMT1/2

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