Preclinical evaluation of dual PI3K-mTOR inhibitors and histone deacetylase inhibitors in head and neck squamous cell carcinoma

Erlich, Rafael B.; Kherrouche, Zoulika; Rickwood, Danny; Endo‐Munoz, Liliana; Cameron, Sarina; Dahler, Alison; Hazar-Rethinam, Mehlika; Long, Lilia Merida de; Wooley, K; Guminski, Alexander; Saunders, Nicholas A.

doi:10.1038/bjc.2011.495

Cited by 55 publications

(59 citation statements)

References 41 publications

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“…An examination of the potential value of PI3K/mTOR inhibitors alone or in combination with histone deacetylase (HDAC) inhibitors in an in vitro model of SCCHN revealed marked enhancement of HDAC inhibitor-induced cytotoxicity by PI3K, AKT, and dual PI3K-mTOR inhibitors [49]. This effect correlated with AKT inhibition and was attenuated by expression of constitutively active AKT.…”

Section: Dual Pi3k/mtor Inhibitionmentioning

confidence: 99%

“…Buparlisib demonstrates synergistic activity with cytotoxic and targeted agents [46,47], and enhances sensitivity to these drugs in resistant cancer models [48]. Buparlisib has also been shown to enhance the in vitro cytotoxicity of histone deacetylase inhibitors in SCCHN cancer cells and to inhibit tumor growth in xenograft models of SCCHN [49]. PX-866 is another agent that has demonstrated antitumor efficacy in SCCHN models with PIK3CA alterations [45].…”

Section: Pan-pi3k Inhibitionmentioning

confidence: 99%

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Targeting the PI3K/AKT/mTOR pathway in squamous cell carcinoma of the head and neck

2015

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Section: Dual Pi3k/mtor Inhibitionmentioning

confidence: 99%

Section: Pan-pi3k Inhibitionmentioning

confidence: 99%

Targeting the PI3K/AKT/mTOR pathway in squamous cell carcinoma of the head and neck

2015

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“…HDAC inhibitors may therefore also be useful for the treatment of those HNSCC that show overexpression of Ano1 and concomitant activation of cyclin D1 [23]. In fact, HDAC inhibitors have already entered preclinical evaluation [42,43]. In recent experiments, we found that pronounced expression of Ano1 in the HNSCC cell line BHY was largely inhibited by treatment with the HDCA inhibitors valproic acid or butyric acid, along with inhibition of cell survival and Ano1-dependent whole cell currents ( figure 3a-f ) rstb.royalsocietypublishing.org Phil.…”

Section: Regulation Of Expression Of Ano1 By Histone Deacetylase and mentioning

confidence: 99%

Role of anoctamins in cancer and apoptosis

Wanitchakool

Wolf

Koehl

et al. 2014

Phil. Trans. R. Soc. B

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Anoctamin 1 (TMEM16A, Ano1) is a recently identified Ca 2+ -activated chloride channel and a member of a large protein family comprising 10 paralogues. Before Ano1 was identified as a chloride channel protein, it was known as the cancer marker DOG1. DOG1/Ano1 is expressed in gastrointestinal stromal tumours (GIST) and particularly in head and neck squamous cell carcinoma, at very high levels never detected in other tissues. It is now emerging that Ano1 is part of the 11q13 locus, amplified in several types of tumour, where it is thought to augment cell proliferation, cell migration and metastasis. Notably, Ano1 is upregulated through histone deacetylase (HDAC), corresponding to the known role of HDAC in HNSCC. As Ano1 does not enhance proliferation in every cell type, its function is perhaps modulated by cell-specific factors, or by the abundance of other anoctamins. Thus Ano6, by regulating Ca 2+ -induced membrane phospholipid scrambling and annexin V binding, supports cellular apoptosis rather than proliferation. Current findings implicate other cellular functions of anoctamins, apart from their role as Ca 2+ -activated Cl − channels.

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“…BGT26 was provided by Novartis, and stocks of BGT226 were prepared as described (16). ZVAD-fmk was added 30 minutes before other treatments.…”

Section: Chemicals and Viability Assaysmentioning

confidence: 99%

RacGAP1 Is a Novel Downstream Effector of E2F7-Dependent Resistance to Doxorubicin and Is Prognostic for Overall Survival in Squamous Cell Carcinoma

Hazar-Rethinam

Long

Gannon

et al. 2015

Molecular Cancer Therapeutics

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We have previously shown that E2F7 contributes to drug resistance in head and neck squamous cell carcinoma (HNSCC) cells. Considering that dysregulation of responses to chemotherapy-induced cytotoxicity is one of the major reasons for treatment failure in HNSCC, identifying the downstream effectors that regulate E2F7-dependent sensitivity to chemotherapeutic agents may have direct clinical impact. We used transcriptomic profiling to identify candidate pathways that contribute to E2F7-dependent resistance to doxorubicin. We then manipulated the expression of the candidate pathway using overexpression and knockdown in in vitro and in vivo models of SCC to demonstrate causality. In addition, we examined the expression of E2F7 and RacGAP1 in a custom tissue microarray (TMA) generated from HNSCC patient samples. Transcriptomic profiling identified RacGAP1 as a potential mediator of E2F7-dependent drug resistance. We validated E2F7-dependent upregulation of RacGAP1 in doxorubicininsensitive SCC25 cells. Extending this, we found that selective upregulation of RacGAP1 induced doxorubicin resistance in previously sensitive KJDSV40. Similarly, stable knockdown of RacGAP1 in insensitive SCC25 cells induced sensitivity to doxorubicin in vitro and in vivo. RacGAP1 expression was validated in a TMA, and we showed that HNSCCs that overexpress RacGAP1 are associated with a poorer patient overall survival. Furthermore, E2F7-induced doxorubicin resistance was mediated via RacGAP1-dependent activation of AKT. Finally, we show that SCC cells deficient in RacGAP1 grow slower and are sensitized to the cytotoxic actions of doxorubicin in vivo. These findings identify RacGAP1 overexpression as a novel prognostic marker of survival and a potential target to sensitize SCC to doxorubicin.

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Preclinical evaluation of dual PI3K-mTOR inhibitors and histone deacetylase inhibitors in head and neck squamous cell carcinoma

Cited by 55 publications

References 41 publications

Targeting the PI3K/AKT/mTOR pathway in squamous cell carcinoma of the head and neck

Targeting the PI3K/AKT/mTOR pathway in squamous cell carcinoma of the head and neck

Role of anoctamins in cancer and apoptosis

RacGAP1 Is a Novel Downstream Effector of E2F7-Dependent Resistance to Doxorubicin and Is Prognostic for Overall Survival in Squamous Cell Carcinoma

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