Abstract 2903: A novel compound induces synthetic lethality for p53 mutations in osteosarcoma cells
| Autor: | Frank J. Schoenen, Mitchell W. Braun, Scott Weir, Alejandro Parrales, Joy M. Fulbright, Melinda Broward, Tyce Bruns, Douglas H. Thamm, Peter R. McDonald, Tomoo Iwakuma, Kathleen A. Neville, Fred Meyer, Shrikant Anant, Jenna Wang, Anuradha Roy, Katherine Chastain, Steve Rogers, Dan A. Dixon |
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| Rok vydání: | 2018 |
| Předmět: | |
| Zdroj: | Cancer Research. 78:2903-2903 |
| ISSN: | 1538-7445 0008-5472 |
| Popis: | Osteosarcoma is the second-highest cause of cancer-related death in children and adolescents. Despite advances in chemotherapy and surgery, the survival rate for metastatic osteosarcoma remains below 30% for the last three decades. Discovery of new chemotherapy agents would be crucial for improving outcomes of osteosarcoma patients. Here, using high-throughput screening, we have found a new compound, called 2-{2-[(3,5-dimethoxybenzyl)sulfanyl]-1,3-thiazol-4-yl}-N-(2-thienylmethyl)acetamide (referred to as KU0171032), as an inducer of apoptosis in various canine and human osteosarcoma cells. This compound shows minimal effects on non-transformed osteoblast and fibroblast cells. Intriguingly, KU0171032-induced apoptosis is more robust in osteosarcoma cells having mutant p53 or null for p53, as compared to cells with wild-type p53. Knockdown of wild-type p53 in U2OS and SJSA-1 cells significantly enhances sensitivity to KU0171032 with increase in DNA damage and caspase-3 cleavage. Moreover, KU0171032 significantly reduces in vivo tumor growth of osteosarcoma cells with p53 knockdown or carrying mutant p53. Our results strongly suggest that KU0171032 shows synthetic lethality with p53 mutations in osteosarcoma cells. Given that loss of p53 activity is frequent event in many cancer types including osteosarcoma while normal cells usually retain wild-type p53, this compound could be used to develop novel therapeutic strategies that capitalize on vulnerabilities in osteosarcoma and other types of cancer. Citation Format: Tomoo Iwakuma, Alejandro Parrales, Peter McDonald, Anuradha Roy, Mitchell W. Braun, Frank J. Schoenen, Jenna Wang, Steve Rogers, Melinda Broward, Tyce Bruns, Shrikant Anant, Dan A. Dixon, Fred Meyer, Katherine M. Chastain, Douglas H. Thamm, Scott J. Weir, Kathleen Neville, Joy M. Fulbright. A novel compound induces synthetic lethality for p53 mutations in osteosarcoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2903. |
| Databáze: | OpenAIRE |
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