scholarly journals PO-503 HDAC inhibitor resistance in colorectal cancer: RAS and AMP; MYC – the partners in crime

2018 ◽  
Author(s):  
S Ispasanie ◽  
S Kistler ◽  
A Heberle ◽  
F Uhlitz ◽  
K Kasack ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Hdac Inhibitor ◽  
Inhibitor Resistance

scholarly journals Checkpoint regulator B7x is epigenetically regulated by HDAC3 and mediates resistance to HDAC inhibitors by reprogramming the tumor immune environment in colorectal cancer

2020 ◽  
Vol 11 (9) ◽  
Author(s):  
Yuxin Li ◽  
Yao Liu ◽  
Na Zhao ◽  
Xiaojun Yang ◽  
Yaqing Li ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Line ◽  
Cancer Cell ◽  
Hdac Inhibitor ◽  
Promoter Region ◽  
Hdac Inhibitors ◽  
Colorectal Cancer Cell ◽  
Colorectal Cancer Cell Line ◽  
Transcription Activator ◽  
Inhibitor Resistance

Abstract HDAC inhibitors are efficacious for treating lymphoma, but display limited efficacy in treating solid tumors. Here, we investigated the relationship between HDAC inhibitor resistance and the tumor immune environment in colorectal cancer. Our data indicated that among the investigated immune factors, B7x expression was enhanced in HDAC inhibitor-resistant colorectal cancer models in vitro and in vivo. In addition, gene manipulation results demonstrated that xenograft mice with tumors derived from a B7x-overexpressing CT-26 colorectal cancer cell line were resistant to HDAC inhibitor treatment. Notably, we found that there is a negative relationship between HDAC and B7x expression in both colorectal cancer cell lines and patients’ tumors. Furthermore, our data indicated that elevated expression of B7x was related to a poor prognosis in colorectal tumor patients. Interestingly, treatment with a specific inhibitor or siRNA of HDAC3, but not HDAC2, 6, and 8, resulted in obvious upregulation of B7x expression in colorectal cancer cells. In addition, our data showed that a cell line with high HDAC3 expression and low B7x expression had decreased enrichment of acetylated histone H3 in the promoter region of the gene encoding B7x. This pattern was reversed by addition of HDAC3 inhibitors. Mechanistically, we found that HDAC3 regulated B7x transcription by promoting the binding of the transcription activator C/EBP-α with the B7x promoter region. Importantly, our data indicated that an antibody neutralizing B7x augmented the response to HDAC inhibitor in the colorectal cancer xenograft model and the lung metastasis model by increasing the ratios of both CD4-positive and CD8-positive T cells. In summary, we demonstrated a role of B7x in HDAC inhibitor resistance and identified the mechanism that dysregulates B7x in colorectal cancer. Our work provides a novel strategy to overcome HDAC inhibitor resistance.

Abstract 4316: Targeting LIFR overcomes HDAC inhibitor resistance in ovarian cancer

2019 ◽  
Author(s):  
Mengxing Li ◽  
Suryavathi Viswanadhapalli ◽  
Gangadhara Reddy Sareddy ◽  
Bindu Santhamma ◽  
Hui Yan ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Hdac Inhibitor ◽  
Inhibitor Resistance

scholarly journals Overactivation of Akt Contributes to MEK Inhibitor Primary and Acquired Resistance in Colorectal Cancer Cells

Cancers ◽  
2019 ◽  
Vol 11 (12) ◽  
pp. 1866 ◽  
Author(s):  
Tsubaki ◽  
Takeda ◽  
Noguchi ◽  
Jinushi ◽  
Seki ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Cells ◽  
Critical Role ◽  
Pik3ca Mutation ◽  
Acquired Resistance ◽  
Mek Inhibitor ◽  
Blue Dye ◽  
Colorectal Cancer Cells ◽  
Inhibitor Resistance ◽  
Ht 29

RAS and BRAF-mutated colorectal cancers are associated with resistance to chemotherapy and poor prognosis, highlighting the need for new therapeutic strategies. Although these cancers sometimes respond to mitogen activated protein kinase kinase (MEK) inhibitor treatment, they often acquire resistance via mechanisms, which are poorly understood. Here, we investigated the mechanism of MEK inhibitor resistance in primary- and acquired-resistant cells. Cell viability was examined using the trypan blue dye exclusion assay. Protein expression was analyzed by western blotting. Somatic mutations in colorectal cancer cells were investigated using the polymerase chain reaction array. PD0325901 and trametinib induced cell death in LoVo and Colo-205 cells but not in DLD-1 and HT-29 cells, which have a PIK3CA mutation constitutively activating Akt and NF-κB. Treatment with PD0325901 and trametinib suppressed ERK1/2 activation in all four cell lines but only induced Akt and NF-κB activation in DLD-1 and HT-29 cells. Inhibition of Akt but not NF-κB, overcame MEK inhibitor resistance in DLD-1 and HT-29 cells. Acquired-resistant LoVo/PR, Colo-205/PR and LoVo/TR cells have constitutively active Akt due to a M1043V mutation in the kinase activation loop of PIK3CA and Akt inhibitor resensitized these cells to MEK inhibitor. These results demonstrate that the overactivation of Akt plays a critical role in MEK inhibitor primary and acquired resistance and implicate combined Akt/MEK inhibition as a potentially useful treatment for RAS/BRAF-mutated colorectal cancer.

Abstract 4316: Targeting LIFR overcomes HDAC inhibitor resistance in ovarian cancer

2019 ◽  
Author(s):  
Mengxing Li ◽  
Suryavathi Viswanadhapalli ◽  
Gangadhara Reddy Sareddy ◽  
Bindu Santhamma ◽  
Hui Yan ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Hdac Inhibitor ◽  
Inhibitor Resistance

Molecular and Biological Characteristics of Acquired Vorinostat-Resistant Cutaneous T-Cell Lymphoma Cells.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1732-1732
Author(s):  
Chunlei Zhang ◽  
Xiang Zhang ◽  
Baoqiang Li ◽  
Madeleine Duvic
Keyword(s):  
T Cell ◽  
Cell Line ◽  
Hdac Inhibitor ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Biological Characteristics ◽  
T Cell Lymphoma ◽  
Class I ◽  
Cutaneous T Cell Lymphoma ◽  
Inhibitor Resistance

Abstract Abstract 1732 Poster Board I-758 Vorinostat (suberoylanilide hydroxamic acid, SAHA), a pan-histone deacetylase (HDAC) inhibitor, has an overall response rate of 24-30% in two phase II studies of patients with cutaneous T cell lymphoma (CTCL). Since a considerable proportion of CTCL patients did not reach a partial response and loss of response could occur after only a few months, development of resistance became an important clinical problem. Although we have shown that constitutive activation of STAT signaling may be involved in resistance to vorinostat, the other mechanisms of resistance to vorinostat in CTCL are largely unknown. To further investigate mechanisms of vorinostat resistance, we have generated a vorinostat-resistant CTCL cell line (HH/VOR) from a parent vorinostat-sensitive HH CTCL cell line by long term exposure to stepwise increasing concentrations of vorinostat. The HH parental cells were cultured in increasing concentrations of vorinostat starting at 10 nM. Viable cells were then passaged into a higher concentration of vorinostat in 10 nM increments until a concentration of 1 μM vorinostat was reached. The HH/VOR cells were then maintained in complete RPMI1640 medium containing 1 μM vorinostat. We studied the molecular and biological characteristics of the vorinostat-resistant CTCL cells. Compared with the parental vorinostat-sensitive HH cells, the vorinostat-resistant HH/VOR cells were highly resistant to vorinostat-mediated growth inhibition and apoptosis. Of interest, the HH/VOR also exhibited cross resistance to another pan-HDAC inhibitor panobinostat and a class I HDAC inhibitor SNDX-275. The vorinostat-resistant HH/VOR cells had reduced accumulation of acetylated histones (H3 & H4) and decreased expression of class I and class II HDACs (1-11), and no expression of multi-drug resistant (MDR) efflux transporters. Moreover, the vorinostat-resistant HH/VOR cells had elevated DNA binding of NF-κB and increased expression of phospho-NF-κB p65 and phospho-STAT-1 compared with the parent sensitive HH cells. Co-treatment with the RXR-selective retinoid bexarotene selectively enhanced vorinostat-induced apoptosis in the vorinostat-sensitive HH and -resistant HH/VOR CTCL cell lines as well as in patients' Sézary cells compared to normal CD4+ T-cells. Taken together, our findings provide further evidence for the potential of vorinostat to cause acquisition of HDAC inhibitor resistance in CTCL. This acquired HDAC inhibitor resistance neither correlates with over-expression of HDACs nor with expression of MDR but correlates with abnormal activation of the NF-κB and STAT-1. Bexarotene may override this acquired resistance of CTCL cells to vorinostat and other HDAC inhibitors. Disclosures Zhang: Merck: Research Funding. Duvic:Merck: Honoraria, Research Funding, Speakers Bureau.

scholarly journals Stromal induction of BRD4 phosphorylation Results in Chromatin Remodeling and BET inhibitor Resistance in Colorectal Cancer

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Wenyu Wang ◽  
Yen-An Tang ◽  
Qian Xiao ◽  
Wee Chyan Lee ◽  
Bing Cheng ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Chromatin Remodeling ◽  
Cancer Drug ◽  
Bet Inhibitor ◽  
Cancer Associated Fibroblast ◽  
Bet Inhibitors ◽  
Inhibitor Resistance ◽  
Bet Protein

AbstractBRD4, a Bromodomain and Extraterminal (BET) protein family member, is a promising anti-cancer drug target. However, resistance to BET inhibitors targeting BRD4 is common in solid tumors. Here, we show that cancer-associated fibroblast (CAF)-activated stromal signaling, interleukin-6/8-JAK2, induces BRD4 phosphorylation at tyrosine 97/98 in colorectal cancer, resulting in BRD4 stabilization due to interaction with the deubiquitinase UCHL3. BRD4 phosphorylation at tyrosine 97/98 also displays increased binding to chromatin but reduced binding to BET inhibitors, resulting in resistance to BET inhibitors. We further show that BRD4 phosphorylation promotes interaction with STAT3 to induce chromatin remodeling through concurrent binding to enhancers and super-enhancers, supporting a tumor-promoting transcriptional program. Inhibition of IL6/IL8-JAK2 signaling abolishes BRD4 phosphorylation and sensitizes BET inhibitors in vitro and in vivo. Our study reveals a stromal mechanism for BRD4 activation and BET inhibitor resistance, which provides a rationale for developing strategies to treat CRC more effectively.

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