&lt;p&gt;Akt/mTOR-Mediated Autophagy Confers Resistance To BET Inhibitor JQ1 In Ovarian Cancer [Corrigendum]&lt;/p&gt;

Luan, Wenqing; Pang, Yingxin; Li, Rui; Xuan, Wei; Jiao, Xiaoxiao; Shi, Juanjuan; Yu, Jiangtao; Mao, Hongluan; Liu, Peishu

doi:10.2147/ott.s236659

Cited by 4 publications

(5 citation statements)

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“…Interestingly, interferon signaling which is significantly attenuated in our JQ1-treated tumors is highly correlated with sensitivity to JQ1, suggesting a possible higher dependence of the sensitive clones on these pathways. Conversely resistance is associated with higher levels of unfolded protein response and mTOR signaling consistent with a known role of mTOR-mediated autophagy in resistance to JQ1 (Luan et al, 2019), and cytotoxic synergy between PI3K/mTOR inhibitors and BET inhibitors (Lee et al, 2015; Stratikopoulos et al, 2015).…”

Section: Resultsmentioning

confidence: 58%

Clonal transcriptomics identifies mechanisms of chemoresistance and empowers rational design of combination therapies

Wild

Cannell

Kania

et al. 2021

Preprint

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Tumour heterogeneity is thought to be a major barrier to successful cancer treatment due to the presence of drug resistant clonal lineages. However, identifying the characteristics of such lineages that underpin resistance to therapy has remained challenging. Here we present WILD-seq; Wholistic Interrogation of Lineage Dynamics by sequencing, a platform that leverages expressed barcodes to simultaneously map clonal identities and transcriptional states at single cell resolution. Our optimised pipeline ensures recurrent representation of clonal lineages across animals and samples, facilitating analysis of clonal dynamics under perturbation. Application of WILD-seq to two triple negative mammary carcinoma mouse models, identified changes in clonal abundance, gene expression and microenvironment in response to JQ1 or taxane chemotherapy. WILD-seq reveals oxidative stress protection as a major mechanism of taxane resistance that renders our tumour models collaterally sensitive to non-essential amino acid deprivation. In summary, WILD-seq enables facile coupling of lineage and gene expression in vivo to elucidate clone-specific pathways of resistance to cancer therapies.

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Section: Resultsmentioning

confidence: 58%

Clonal transcriptomics identifies mechanisms of chemoresistance and empowers rational design of combination therapies

Wild

Cannell

Kania

et al. 2021

Preprint

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“…This is because autophagy has two opposite roles in tumour cells: cytoprotective and cytotoxic 67 . In ovarian cancer and acute myeloid leukaemia in humans, JQ1‐induced autophagy had a cytoprotective role and an autophagy inhibitor enhanced the anti‐tumour effect of JQ1 68,69 . Conversely, in human bladder cancer cell lines, the proliferation suppression capacity of JQ1 was attenuated by autophagy inhibitors, which suggested that JQ1‐induced autophagy had a cytotoxic role 23 .…”

Section: Discussionmentioning

confidence: 99%

“…67 In ovarian cancer and acute myeloid leukaemia in humans, JQ1-induced autophagy had a cytoprotective role and an autophagy inhibitor enhanced the anti-tumour effect of JQ1. 68,69 Conversely, in human bladder cancer cell lines, the proliferation suppression capacity of JQ1 was attenuated by autophagy inhibitors, which suggested that JQ1-induced autophagy had a cytotoxic role. 23 Further experiments are needed to elucidate which roles JQ1-induced autophagy has in HSA.…”

Section: Discussionmentioning

confidence: 99%

Manipulating histone acetylation leads to antitumor effects in hemangiosarcoma cells

Suzuki

Aoshima

Yamazaki

et al. 2022

Vet Comparative Oncology

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Canine hemangiosarcoma (HSA) is a malignant tumour derived from endothelial cells. No effective treatment has yet been developed because of the lack of understanding of its pathogenesis. Histone acetylation, an epigenetic modification, is highly associated with cancer pathogenesis. Manipulating histone acetylation by histone deacetylase inhibitors (HDACi) or bromodomain and extraterminal domain inhibitors (BETi) is one approach to treat various cancers. However, the role of histone acetylation in HSA remains unknown. This study aimed to investigate how histone acetylation functions in HSA pathogenesis using two HDACi, suberanilohydroxamic acid (SAHA) and valproic acid (VPA), and one BETi, JQ1, in vitro and in vivo. Histone acetylation levels were high in cell lines and heterogeneous in clinical cases. SAHA and JQ1 induced apoptosis in HSA cell lines. HSA cell lines treated with SAHA and VPA upregulated inflammatory‐related genes and attracted macrophage cell line RAW264 cells, which suggests that SAHA and VPA can affect immune responses. JQ1 stimulated autophagy and inhibited the cell cycle in HSA cell lines. Finally, we demonstrated that JQ1 suppressed HSA tumour cell proliferation in vivo although SAHA and VPA did not affect tumour growth. These results suggest that BETi can be alternative drugs for HSA treatment. Although further research is required, our study indicated that dysregulation of histone acetylation is likely to be involved in HSA malignancy.

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“…For TNBC, the cells can rapidly develop resistance due to various mechanisms, including changes in signaling pathways involving ZNF33A upregulation, deletion of SNF/SWI complex components as well as ubiquitination-related genes such as SPOP, UBE2M, CUL3 and USP14 ( 147 , 148 ). In ovarian cancer cell lines, autophagy (shown by increased expression of ATG5 and Beclin1) induced by inactivation of Akt (Ser473)/mTOR (Ser2448) pathway, is linked with resistance to BETi possibly as a way to bypass BET inhibition ( 149 ). Thus, it is essential to note that resistance to JQ1 has distinct mechanisms depending on cancer types; however, increase in Myc expression has been pinpointed as common cause of resistance to BETi ( 147 , 150 , 151 ).…”

Section: Resistance To Bet Inhibitionmentioning

confidence: 99%

Targeting BRD4: Potential therapeutic strategy for head and neck squamous cell carcinoma (Review)

Yongprayoon,

Wattanakul,

Khomate

et al. 2024

Oncol Rep

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As a member of BET (bromodomain and extra-terminal) protein family, BRD4 (bromodomain-containing protein 4) is a chromatin-associated protein that interacts with acetylated histones and actively recruits regulatory proteins, leading to the modulation of gene expression and chromatin remodeling. The cellular and epigenetic functions of BRD4 implicate normal development, fibrosis and inflammation. BRD4 has been suggested as a potential therapeutic target as it is often overexpressed and plays a critical role in regulating gene expression programs that drive tumor cell proliferation, survival, migration and drug resistance. To address the roles of BRD4 in cancer, several drugs that specifically target BRD4 have been developed. Inhibition of BRD4 has shown promising results in preclinical models, with several BRD4 inhibitors undergoing clinical trials for the treatment of various cancers. Head and neck squamous cell carcinoma (HNSCC), a heterogeneous group of cancers, remains a health challenge with a high incidence rate and poor prognosis. Conventional therapies for HNSCC often cause adverse effects to the patients. Targeting BRD4, therefore, represents a promising strategy to sensitize HNSCC to chemo- and radiotherapy allowing de-intensification of the current therapeutic regime and subsequent reduced side effects. However, further studies are required to fully understand the underlying mechanisms of action of BRD4 in HNSCC in order to determine the optimal dosing and administration of BRD4-targeted drugs for the treatment of patients with HNSCC.

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<p>Akt/mTOR-Mediated Autophagy Confers Resistance To BET Inhibitor JQ1 In Ovarian Cancer [Corrigendum]</p>

Abstract: The authors of this paper have advised that when they rechecked their data and figures, they found one mistake in Figure 1C on page 8065. Figure 1C reflects the effects of different concentrations of JQ1 on the apoptosis level.

Cited by 4 publications

References 0 publications

Clonal transcriptomics identifies mechanisms of chemoresistance and empowers rational design of combination therapies

Clonal transcriptomics identifies mechanisms of chemoresistance and empowers rational design of combination therapies

Manipulating histone acetylation leads to antitumor effects in hemangiosarcoma cells

Targeting BRD4: Potential therapeutic strategy for head and neck squamous cell carcinoma (Review)

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