Targeting Wnt Signaling To Overcome PARP Inhibitor Resistance

ABSTRACTEpithelial ovarian cancer (EOC) has one of the highest deaths to incidence ratios. High grade serous ovarian carcinoma (HGSOC) is the most common and deadliest EOC histotype because of the lack of secondary therapeutic options following debulking surgery and platinum/taxane-based chemotherapies. For recurrent chemosensitive HGSOC, poly(ADP)-ribose polymerase inhibitors (PARPi; olaparib, rucaparib, or niraparib) represent an emerging treatment strategy. While PARPi are most effective in homologous recombination DNA repair-deficient (HRD) HGSOCs, more recent studies have observed a significant clinical benefit in non-HRD HGSOCs. However, all HGSOC patients are likely to acquire resistance to PARPi. Therefore, there is an urgent clinical need to better understand PARPi resistance, and to introduce novel combinatorial therapies to overcome PARPi resistance and extend HGSOC disease-free intervals. Utilizing a two BRCA2-mutated and one BRCA-wildtype HGSOC cell lines that are olaparib sensitive, we established resistant cells. Transcriptome analysis of the matched olaparib-sensitive versus resistant cells did not detect BRCA2 reversion mutations, but revealed activation of Wnt/TCF signaling pathway, as TCF transcriptional activity was significantly increased in PARPi-resistant cells. In parallel, forced activation of Wnt signaling in PARPi-sensitive cells via WNT3A stimulation reduced response to PARPi. In a recurrent-HGSOC PARPi insensitive patient-derived xenograft model there was an increase in a Wnt/TCF transcriptional target. PARPi resistant cells were sensitive to inhibition of Wnt signaling using the FDA-approved compound, pyrvinium pamoate, which has been shown to inhibit Wnt signaling. We observed that combining pyrvinium pamoate with olaparib resulted in a significant decrease in tumor burden and number of tumor nodules. This study demonstrates that Wnt signaling can mediate PARPi resistance in HGSOC and provides a clinical rationale for combining PARPi and Wnt inhibitors.

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Abstract GMM-040: TARGETING WNT SIGNALING TO OVERCOME PARP INHIBITOR RESISTANCE

10.1158/1557-3265.ovcasymp18-gmm-040 ◽

2019 ◽

Author(s):

Tomomi M. Yamamoto ◽

Alexandra McMellen ◽

Zachary L. Watson ◽

Jennifer Aguilera ◽

Matthew J. Sikora ◽

...

Keyword(s):

Wnt Signaling ◽

Parp Inhibitor ◽

Inhibitor Resistance

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CMTM6 drives cisplatin resistance in OSCC by regulating AKT mediated Wnt signaling

10.1101/2020.03.18.993774 ◽

2020 ◽

Author(s):

Pallavi Mohapatra ◽

Omprakash Shriwas ◽

Sibasish Mohanty ◽

Sandeep Rai Kaushik ◽

Rakesh Arya ◽

...

Keyword(s):

Cell Death ◽

Wnt Signaling ◽

Tumor Cells ◽

Cisplatin Resistance ◽

Xenograft Model ◽

Tumor Burden ◽

Proteomic Profiling ◽

Drug Induced ◽

Membrane Bound ◽

Induced Apoptosis

AbstractChemoresistance is one of the important factors for treatment failure in OSCC, which can culminate in progressive tumor growth and metastatic spread. Rewiring tumor cells to undergo drug-induced apoptosis is a promising way to overcome chemoresistance, which can be achieved by identifying the causative factors for acquired chemoresistance. In this study, to explore the key cisplatin resistance triggering factors, we performed global proteomic profiling of OSCC lines representing with sensitive, early and late cisplatin-resistant patterns. The top ranked up-regulated protein appeared to be CMTM6. We found CMTM6 to be elevated in both early and late cisplatin-resistant cells with respect to the sensitive counterpart. Analyses of OSCC patient samples indicate that CMTM6 expression is upregulated in chemotherapy-non-responder tumors as compared to chemotherapy-naïve tumors. Stable knockdown of CMTM6 restores cisplatin-mediated cell death in chemoresistant OSCC lines. Similarly, upon CMTM6 overexpression in CMTM6KD lines, the cisplatin resistant phenotype was efficiently rescued. Mechanistically, it was found that CMTM6 interacts with membrane bound Enolase-1 and stabilized its expression, which in turn activates the AKT-GSK3β mediated Wnt signaling. CMTM6 triggers the translocation of β-catenin into the nucleus, which elevates the Wnt target pro-survival genes like Cyclin D, c-Myc and CD44. Moreover, incubation with lithium chloride, a Wnt signaling activator, efficiently rescued the chemoresistant phenotype in CMTM6KD OSCC lines. In a patient-derived cell xenograft model of chemoresistant OSCC, knock-down of CMTM6 restores cisplatin induced cell death and results in significant reduction of tumor burden. CMTM6 has recently been identified as a stabilizer of PD-L1 and henceforth it facilitates immune evasion by tumor cells. Herewith for the first time, we uncovered another novel role of CMTM6 as one of the major driver of cisplatin resistance.

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Combination therapy of the EZH2 inhibitor GSK126 and the PARP inhibitor Olaparib shows in vivo synergy in a patient-derived xenograft model of BRCA1-deficient breast cancer

Geburtshilfe und Frauenheilkunde ◽

10.1055/s-0034-1388546 ◽

2014 ◽

Vol 74 (S 01) ◽

Author(s):

J Puppe ◽

P ter Brugge ◽

M Seressi ◽

O van Tellingen ◽

E van der Burg ◽

...

Keyword(s):

Breast Cancer ◽

Combination Therapy ◽

Parp Inhibitor ◽

Xenograft Model ◽

Patient Derived Xenograft

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Therapeutically actionable signaling node to rescue AURKA driven loss of primary cilia in VHL-deficient cells

Scientific Reports ◽

10.1038/s41598-021-89933-7 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Pratim Chowdhury ◽

Dimuthu Perera ◽

Reid T. Powell ◽

Tia Talley ◽

Durga Nand Tripathi ◽

...

Keyword(s):

Ubiquitin Ligase ◽

Primary Cilia ◽

Mtor Inhibitor ◽

E3 Ubiquitin Ligase ◽

Xenograft Model ◽

Aurora Kinase ◽

Tumor Burden ◽

Aurora Kinase A ◽

Von Hippel Lindau ◽

In Cells

AbstractLoss of primary cilia in cells deficient for the tumor suppressor von Hippel Lindau (VHL) arise from elevated Aurora Kinase A (AURKA) levels. VHL in its role as an E3 ubiquitin ligase targets AURKA for degradation and in the absence of VHL, high levels of AURKA result in destabilization of the primary cilium. We identified NVP-BEZ235, a dual PI3K/AKT and mTOR inhibitor, in an image-based high throughput screen, as a small molecule that restored primary cilia in VHL-deficient cells. We identified the ability of AKT to modulate AURKA expression at the transcript and protein level. Independent modulation of AKT and mTOR signaling decreased AURKA expression in cells confirming AURKA as a new signaling node downstream of the PI3K cascade. Corroborating these data, a genetic knockdown of AKT in cells deficient for VHL rescued the ability of these cells to ciliate. Finally, inhibition of AKT/mTOR using NVP-BEZ235 was efficacious in reducing tumor burden in a 786-0 xenograft model of renal cell carcinoma. These data highlight a previously unappreciated signaling node downstream of the AKT/mTOR pathway via AURKA that can be targeted in VHL-null cells to restore ciliogenesis.

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Warburg effect-promoted exosomal circ_0072083 releasing up-regulates NANGO expression through multiple pathways and enhances temozolomide resistance in glioma

Journal of Experimental & Clinical Cancer Research ◽

10.1186/s13046-021-01942-6 ◽

2021 ◽

Vol 40 (1) ◽

Author(s):

Chenyu Ding ◽

Xuehan Yi ◽

Xiangrong Chen ◽

Zanyi Wu ◽

Honghai You ◽

...

Keyword(s):

Warburg Effect ◽

Lactate Production ◽

Xenograft Model ◽

Cell Counting ◽

Luciferase Reporter ◽

Migration And Invasion ◽

Circular Rnas ◽

Rna Immunoprecipitation ◽

Resistant Cells

Abstract Background Temozolomide (TMZ) resistance limits its application in glioma. Exosome can carry circular RNAs (circRNAs) to regulate drug resistance via sponging microRNAs (miRNAs). miRNAs can control mRNA expression by regulate the interaction with 3’UTR and methylation. Nanog homeobox (NANOG) is an important biomarker for TMZ resistance. Hitherto, it is unknown about the role of exosomal hsa_circ_0072083 (circ_0072083) in TMZ resistance in glioma, and whether it is associated with NANOG via regulating miRNA sponge and methylation. Methods TMZ-resistant (n = 36) and sensitive (n = 33) patients were recruited. The sensitive cells and constructed resistant cells were cultured and exposed to TMZ. circ_0072083, miR-1252-5p, AlkB homolog H5 (ALKBH5) and NANOG levels were examined via quantitative reverse transcription polymerase chain reaction and western blot. The half maximal inhibitory concentration (IC50) of TMZ, cell proliferation, apoptosis, migration and invasion were analyzed via Cell Counting Kit-8, colony formation, flow cytometry, wound healing and transwell assays. The in vivo function was assessed using xenograft model. The N6-methyladenosine (m6A) level was analyzed via methylated RNA immunoprecipitation (MeRIP). Target relationship was investigated via dual-luciferase reporter assay and RNA immunoprecipitation. Warburg effect was investigated via lactate production, glucose uptake and key enzymes expression. Exosome was isolated and confirmed via transmission electron microscopy and specific protein expression. Results circ_0072083 expression was increased in TMZ-resistant glioma tissues and cells. circ_0072083 knockdown restrained the resistance of resistant cells via decreasing IC50 of TMZ, proliferation, migration, invasion and xenograft tumor growth and increasing apoptosis. circ_0072083 silence reduced NANOG expression via blocking ALKBH5-mediated demethylation. circ_0072083 could regulate NANOG and ALKBH5 via targeting miR-1252-5p to control TMZ resistance. Warburg effect promoted the release of exosomal circ_0072083 in resistant cells. Exosomal circ_0072083 from resistant cells increased the resistance of sensitive cells to TMZ in vitro and xenograft model. Exosomal circ_0072083 level was enhanced in resistant patients, and it had a diagnostic value and indicated a lower overall survival in glioma. Conclusion Exosomal circ_0072083 promoted TMZ resistance via increasing NANOG via regulating miR-1252-5p-mediated degradation and demethylation in glioma.

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Abstract 2052: TRIP13 amplification confers PARP inhibitor resistance and polymerase theta inhibitor sensitivity

10.1158/1538-7445.am2021-2052 ◽

2021 ◽

Author(s):

Jeffrey Patterson-Fortin ◽

Jia Zhou ◽

Alan D'Andrea

Keyword(s):

Parp Inhibitor ◽

Inhibitor Resistance

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Serum CEACAM1 Elevation Correlates with Melanoma Progression and Failure to Respond to Adoptive Cell Transfer Immunotherapy

Journal of Immunology Research ◽

10.1155/2015/902137 ◽

2015 ◽

Vol 2015 ◽

pp. 1-8 ◽

Cited By ~ 4

Author(s):

R. Ortenberg ◽

S. Sapoznik ◽

D. Zippel ◽

R. Shapira-Frommer ◽

O. Itzhaki ◽

...

Keyword(s):

Strong Predictor ◽

Xenograft Model ◽

Tumor Burden ◽

Adoptive Cell Transfer ◽

Screening Tools ◽

Response To Treatment ◽

Tumor Biomarker ◽

Melanoma Patients ◽

First Time

Malignant melanoma is a devastating disease whose incidences are continuously rising. The recently approved antimelanoma therapies carry new hope for metastatic patients for the first time in decades. However, the clinical management of melanoma is severely hampered by the absence of effective screening tools. The expression of the CEACAM1 adhesion molecule on melanoma cells is a strong predictor of poor prognosis. Interestingly, a melanoma-secreted form of CEACAM1 (sCEACAM1) has recently emerged as a potential tumor biomarker. Here we add novel evidences supporting the prognostic role of serum CEACAM1 by using a mice xenograft model of human melanoma and showing a correlation between serum CEACAM1 and tumor burden. Moreover, we demonstrate that serum CEACAM1 is elevated over time in progressive melanoma patients who fail to respond to immunotherapy as opposed to responders and stable disease patients, thus proving a correlation between sCEACAM1, response to treatment, and clinical deterioration.

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Increasing Wnt signaling in the bone marrow microenvironment inhibits the development of myeloma bone disease and reduces tumor burden in bone in vivo

Blood ◽

10.1182/blood-2007-03-077685 ◽

2008 ◽

Vol 111 (5) ◽

pp. 2833-2842 ◽

Cited By ~ 118

Author(s):

Claire M. Edwards ◽

James R. Edwards ◽

Seint T. Lwin ◽

Javier Esparza ◽

Babatunde O. Oyajobi ◽

...

Keyword(s):

Bone Marrow ◽

Tumor Growth ◽

Wnt Signaling ◽

Bone Disease ◽

Critical Role ◽

Tumor Burden ◽

Bone Marrow Microenvironment ◽

Myeloma Bone Disease ◽

Osteolytic Bone Disease

There is increasing evidence to suggest that the Wnt signaling pathway plays a critical role in the pathogenesis of myeloma bone disease. In the present study, we determined whether increasing Wnt signaling within the bone marrow microenvironment in myeloma counteracts development of osteolytic bone disease. C57BL/KaLwRij mice were inoculated intravenously with murine 5TGM1 myeloma cells, resulting in tumor growth in bone and development of myeloma bone disease. Lithium chloride (LiCl) treatment activated Wnt signaling in osteoblasts, inhibited myeloma bone disease, and decreased tumor burden in bone, but increased tumor growth when 5TGM1 cells were inoculated subcutaneously. Abrogation of β-catenin activity and disruption of Wnt signaling in 5TGM1 cells by stable overexpression of a dominant-negative TCF4 prevented the LiCl-induced increase in subcutaneous growth but had no effect on LiCl-induced reduction in tumor burden within bone or on osteolysis in myeloma-bearing mice. Together, these data highlight the importance of the local microenvironment in the effect of Wnt signaling on the development of myeloma bone disease and demonstrate that, despite a direct effect to increase tumor growth at extraosseous sites, increasing Wnt signaling in the bone marrow microenvironment can prevent the development of myeloma bone disease and inhibit myeloma growth within bone in vivo.

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