TDP1 and PARP1 Deficiency Are Cytotoxic to Rhabdomyosarcoma Cells

Fam, Hok Khim; Walton, Cheryl; Mitra, Sheetal A.; Chowdhury, Miraj Kobad; Osborne, Nichola; Choi, Kunho; Sun, Guobin; Wong, Patrick C.W.; O’Sullivan, Maureen; Turashvili, Gulisa; Aparicio, Samuel; Triche, Timothy J.; Bond, Mason; Pallen, Catherine J.; Boerkoel, Cornelius F.

doi:10.1158/1541-7786.mcr-12-0575

Cited by 37 publications

(45 citation statements)

References 51 publications

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“…Tdp1 expression is increased in several specific types of cancers including non-small cell lung cancers (58), Dukes C colorectal cancers (57), breast cancer cell lines (89), and some RMSs (56). We show that high levels of CIN in RH30 RMS cells can be partially rescued by the knockdown of TDP1 (Fig.…”

Section: Rms Lines Expressingmentioning

confidence: 68%

“…To further explore the link between increased hTdp1 expression and CIN, we focused on RMS, one of the most common soft tissue sarcomas in children (59). Some RMS tumors have elevated hTdp1 at both the mRNA and protein levels (56). Using metaphase spreads, we examined whether elevated hTdp1 levels caused CIN in RMS cells by comparing chromosomal abnormalities in RH30 cells, which have high levels of Tdp1 relative to control human skeletal muscle (HSM) cells (56).…”

Section: Rms Lines Expressingmentioning

confidence: 99%

“…Cell proliferation and viability were measured as previously described (56). Refer to SI Materials and Methods for more details.…”

Section: Sdl Screens and Confirmationsmentioning

confidence: 99%

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Overexpression screens identify conserved dosage chromosome instability genes in yeast and human cancer

Duffy

Fam

Wang

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Somatic copy number amplification and gene overexpression are common features of many cancers. To determine the role of gene overexpression on chromosome instability (CIN), we performed genome-wide screens in the budding yeast for yeast genes that cause CIN when overexpressed, a phenotype we refer to as dosage CIN (dCIN), and identified 245 dCIN genes. This catalog of genes reveals human orthologs known to be recurrently overexpressed and/or amplified in tumors. We show that two genes, TDP1, a tyrosyl-DNA-phosphdiesterase, and TAF12, an RNA polymerase II TATA-box binding factor, cause CIN when overexpressed in human cells. Rhabdomyosarcoma lines with elevated human Tdp1 levels also exhibit CIN that can be partially rescued by siRNA-mediated knockdown of TDP1. Overexpression of dCIN genes represents a genetic vulnerability that could be leveraged for selective killing of cancer cells through targeting of an unlinked synthetic dosage lethal (SDL) partner. Using SDL screens in yeast, we identified a set of genes that when deleted specifically kill cells with high levels of Tdp1. One gene was the histone deacetylase RPD3, for which there are known inhibitors. Both HT1080 cells overexpressing hTDP1 and rhabdomyosarcoma cells with elevated levels of hTdp1 were more sensitive to histone deacetylase inhibitors valproic acid (VPA) and trichostatin A (TSA), recapitulating the SDL interaction in human cells and suggesting VPA and TSA as potential therapeutic agents for tumors with elevated levels of hTdp1. The catalog of dCIN genes presented here provides a candidate list to identify genes that cause CIN when overexpressed in cancer, which can then be leveraged through SDL to selectively target tumors.dosage chromosome instability | overexpression | synthetic dosage lethality | TDP1 | rhabdomyosarcoma

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Section: Rms Lines Expressingmentioning

confidence: 68%

Section: Rms Lines Expressingmentioning

confidence: 99%

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Overexpression screens identify conserved dosage chromosome instability genes in yeast and human cancer

Duffy

Fam

Wang

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Talazoparib as a single agent was not active against Ewing sarcoma xenografts (56). Rhabdomyosarcoma also tend to high in PARP1 (Figure 6) (57). Expression of polo-like kinase 2 (PLK2) and miRs -100, -574, -22, -21 and -30 were negatively correlated with talazoparib sensitivity (Figure 6).…”

Section: Discussionmentioning

confidence: 99%

Sarcoma Cell Line Screen of Oncology Drugs and Investigational Agents Identifies Patterns Associated with Gene and microRNA Expression

Teicher

Polley

Kunkel

et al. 2015

Molecular Cancer Therapeutics

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The diversity in sarcoma phenotype and genotype make treatment of this family of diseases exceptionally challenging. Sixty-three human adult and pediatric sarcoma lines were screened with 100 FDA approved oncology agents and 345 investigational agents. The investigational agents library enabled comparison of several compounds targeting the same molecular entity allowing comparison of target specificity and heterogeneity of cell line response. Gene expression was derived from exon array data and microRNA expression was derived from direct digital detection assays. The compounds were screened against each cell line at 9 concentrations in triplicate with an exposure time of 96 hrs using Alamar blue as the endpoint. Results are presented for inhibitors of the following targets: aurora kinase, IGF-1R, MEK, BET bromodomain, and PARP1. Chemical structures, IC50 heat maps, concentration response curves, gene expression and miR expression heat maps are presented for selected examples. In addition, two cases of exceptional responders are presented. The drug and compound response, gene expression and microRNA expression data are publicly available at http://sarcoma.cancer.gov. These data provide a unique resource to the cancer research community.

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“…Furthermore, it was reported that the decrease in RAD51 levels led to increased levels of g-H2AX expression and cleavage of PARP. In a research endeavor relating to soft tissue sarcoma and rhabdomyosarcoma (RMS), Fam and coworkers have demonstrated that increased levels of expression of TDP1 and PARP1 were observed in RMS [48]. Various experiments were conducted to identify the resistance to a camptothecin analog, irinotecan, which was due to overexpression of TDP1 and further knockdown of TDP1 sensitized the RMS to irinotecan.…”

Section: Parp Inhibitors In Dna Damage Responsementioning

confidence: 99%

Embracing synthetic lethality of novel anticancer therapies

Kamal¹,

Shaik

Malik

2015

Expert Opinion on Drug Discovery

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Most of the currently used chemotherapeutic agents will destroy cells irrespective of whether they are cancer cells or fast growing normal cells; but SL is one of the approaches being developed with potential as a selective cancer therapy. PARP inhibitors, such as olaparib, are useful in BRCA mutated cancer cells and are also used in combination with other drug to enhance their efficacy. Research on PARP inhibitors is progressing at a good pace but there are still some significant challenges that must be addressed.

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TDP1 and PARP1 Deficiency Are Cytotoxic to Rhabdomyosarcoma Cells

Abstract: Selective targeting of TDP1 and/or PARP-1 in rhabdomyosarcoma induces cytotoxicity and sensitizes to DNA damaging agents.

Cited by 37 publications

References 51 publications

Overexpression screens identify conserved dosage chromosome instability genes in yeast and human cancer

Overexpression screens identify conserved dosage chromosome instability genes in yeast and human cancer

Sarcoma Cell Line Screen of Oncology Drugs and Investigational Agents Identifies Patterns Associated with Gene and microRNA Expression

Embracing synthetic lethality of novel anticancer therapies

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