TTK inhibition radiosensitizes basal-like breast cancer through impaired homologous recombination

Increased rates of locoregional recurrence are observed in patients with basal-like breast cancer (BC) despite the use of radiation therapy (RT); therefore, approaches that result in radiosensitization of basal-like BC are critically needed. Using patients’ tumor gene expression data from 4 independent data sets, we correlated gene expression with recurrence to find genes significantly correlated with early recurrence after RT. The highest-ranked gene, TTK, was most highly expressed in basal-like BC across multiple data sets. Inhibition of TTK by both genetic and pharmacologic methods enhanced radiosensitivity in multiple basal-like cell lines. Radiosensitivity was mediated, at least in part, through persistent DNA damage after treatment with TTK inhibition and RT. Inhibition of TTK impaired homologous recombination (HR) and repair efficiency, but not nonhomologous end-joining, and decreased the formation of Rad51 foci. Reintroduction of wild-type TTK rescued both radioresistance and HR repair efficiency after TTK knockdown, however, reintroduction of kinase-dead TTK did not. In vivo, TTK inhibition combined with RT led to a significant decrease in tumor growth in both heterotopic and orthotopic, including patient-derived xenograft, BC models. These data support the rationale for clinical development of TTK inhibition as a radiosensitizing strategy for patients with basal-like BC, and efforts toward this end are currently underway.
Source: Journal of Clinical Investigation - Category: Biomedical Science Authors: Source Type: research

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RARITAN, N.J., February 3, 2020 – The Janssen Pharmaceutical Companies of Johnson &Johnson announced today multiple data presentations from a robust solid tumor portfolio that will be featured at the American Society of Clinical Oncology Genitourinary (ASCO GU) Cancers Symposium, taking place February 13-15 in San Francisco. Company-sponsored data presentations will include clinical results for ERLEADA® (apalutamide) and niraparib in prostate cancer; and BALVERSA™ (erdafitinib) in bladder cancer. “We are committed to improving outcomes in patients with prostate and bladder cancer where high unmet ...
Source: Johnson and Johnson - Category: Pharmaceuticals Tags: Innovation Source Type: news
Genetic variations in DNA damage repair (DDR) genes may influence radiation therapy (RT) –induced acute normal tissue toxicity in patients with breast cancer. Identifying an individual or multiple single-nucleotide polymorphisms (SNPs) associated with RT–induced early adverse skin reactions (EASR) is critical for precision medicine in radiation oncology.
Source: International Journal of Radiation Oncology * Biology * Physics - Category: Radiology Authors: Tags: Clinical Investigation Source Type: research
Abstract PURPOSE: Genetic variations in DNA damage repair (DDR) genes may influence radiation therapy (RT)-induced acute normal tissue toxicity in patients with breast cancer. Identifying an individual or multiple single-nucleotide polymorphisms (SNPs) associated with RT-induced early adverse skin reactions (EASR) is critical for precision medicine in radiation oncology. METHODS AND MATERIALS: At the completion of RT, EASR was assessed using the Oncology Nursing Society scale (0-6) in 416 patients with breast cancer, and Oncology Nursing Society score ≥4 was considered RT-induced EASR. PLINK set-based test...
Source: Physics in Medicine and Biology - Category: Physics Authors: Tags: Int J Radiat Oncol Biol Phys Source Type: research
ConclusionsPRDR radiation therapy with capecitabine was a well-tolerated and effective method for treating patients with recurrent breast cancer. Prospective studies are necessary to compare side effects and efficacy with conventional dose rate reirradiation and to evaluate the potential role for capecitabine in the recurrent setting.
Source: Practical Radiation Oncology - Category: Cancer & Oncology Source Type: research
ConclusionsPRDR radiation therapy with capecitabine were well tolerated and effective method for treating patients with recurrent breast cancer. Prospective studies are necessary to compare side effects and efficacy with conventional dose rate re-irradiation, as well as, to evaluate the potential role for capecitabine in the recurrent setting.
Source: Practical Radiation Oncology - Category: Cancer & Oncology Source Type: research
Antonio Lucena-Cacace1, Masayuki Umeda1, Lola E. Navas2,3 and Amancio Carnero2,3* 1Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan 2CIBERONC, ISCIII, Madrid, Spain 3Instituto de Biomedicina de Sevilla (IBIS), Hospital Universitario Virgen del Rocío (HUVR), CSIC, Universidad de Sevilla, Sevilla, Spain Glioma Cancer Stem-Like Cells (GSCs) are a small subset of CD133+ cells with self-renewal properties and capable of initiating new tumors contributing to Glioma progression, maintenance, hierarchy, and complexity. GSCs are highly res...
Source: Frontiers in Oncology - Category: Cancer & Oncology Source Type: research
This study was carried out in accordance with the recommendations of international guidelines and ethical standards with written informed consent from all subjects. All subjects gave written informed consent in accordance with the Declaration of Helsinki. The protocol was approved by the Institutional Ethics Committee of Kunming General Hospital, China. miRNAs, Plasmids, Transfection, and Irradiation To predict miRNAs with potential binding sites in the 3′UTR of PHLDA2, Targetscan (http://www.targetscan.org/), miRanda (http://www.microrna.org/), and Diana database (http://diana.cslab,ece.nura.gr/) algorithms were u...
Source: Frontiers in Oncology - Category: Cancer & Oncology Source Type: research
This study was supported by the Shanghai Sailing Program [grant number 17YF1425200, 2017]; Chinese National Natural Science Funding [grant number 81702249, 2017]; Science and Technology Commission of Shanghai Municipality [grant number 17511103403, 2017]; The funder has no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. Conflict of Interest Statement The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Acknowledgments We acknowledge the ex...
Source: Frontiers in Oncology - Category: Cancer & Oncology Source Type: research
Rinat Bar-Shalom1, Margalit Bergman2, Shlomo Grossman2, Naiel Azzam1, Lital Sharvit1 and Fuad Fares1* 1Department of Human Biology, Faculty of Natural Sciences, University of Haifa, Haifa, Israel 2Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel Colorectal cancer (CRC) is the second most common cancer in females and the third in males worldwide. Conventional therapy of CRC is limited by severe side effects and by the development of resistance. Therefore, additional therapies are needed in order to combat the problem of selectivity and drug resistance in CRC patients. Inula viscosa (IV) is a well-...
Source: Frontiers in Oncology - Category: Cancer & Oncology Source Type: research
Radiation therapy can have adverse effects on normal tissue and cause chronic ulcers. The purpose of this study was to compare breast cancer patients who underwent single-stage reconstruction with patients who underwent 2-stage reconstruction for chronic radiation-induced necrotic ulcers of the chest wall. This retrospective study comprised of 50 patients with chronic radiation-induced chest wall ulcers who underwent chest wall reconstruction in our hospital between January 2002 and January 2016. All patients developed ulcers after undergoing breast cancer surgery, followed by radiation therapy. These patients were divide...
Source: Medicine - Category: Internal Medicine Tags: Research Article: Observational Study Source Type: research
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