Strong synergy with APR-246 and DNA-damaging drugs in primary cancer cells from patients with TP53 mutant High-Grade Serous ovarian cancer

• Published in: Journal of ovarian research Vol. 9; no. 1; p. 27
• Main Authors: Fransson, Åsa, Glaessgen, Daria, Alfredsson, Jessica, Wiman, Klas G, Bajalica-Lagercrantz, Svetlana, Mohell, Nina
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 14.05.2016; BioMed Central
• Subjects: Analysis; Antineoplastic Agents - pharmacology; Cancer; Cell Survival - drug effects; Cisplatin - pharmacology; Cystadenocarcinoma, Serous - drug therapy; Cystadenocarcinoma, Serous - genetics; Cystadenocarcinoma, Serous - pathology; DNA damage; DNA Damage - drug effects; Drug Resistance, Neoplasm - genetics; Drug Synergism; Drug therapy; Female; Genetic aspects; Health aspects; Humans; Inhibitory Concentration 50; Medicin och hälsovetenskap; Mutation; Neoplasm Grading; Neoplasm Staging; Ovarian cancer; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - genetics; Ovarian Neoplasms - pathology; Quinuclidines - pharmacology; Tumor proteins; Tumor Suppressor Protein p53 - genetics; Sweden; High-Grade Serous (HGS) cancer; APR-246 (PRIMA-1MET); p53 reactivation; DNA-damaging drugs; Primary cancer cells; Synergy; Doxorubicin; TP53 mutation; Cisplatin; Ovarian cancer
• DOI: 10.1186/s13048-016-0239-6
• ISSN: 1757-2215

Mutation in the tumor suppressor gene TP53 is an early event in the development of high-grade serous (HGS) ovarian cancer and is identified in more than 96 % of HGS cancer patients. APR-246 (PRIMA-1(MET)) is the first clinical-stage compound that reactivates mutant p53 protein by refolding it to wild type conformation, thus inducing apoptosis. APR-246 has been tested as monotherapy in a Phase I/IIa clinical study in hematological malignancies and prostate cancer with promising results, and a Phase Ib/II study in combination with platinum-based therapy in ovarian cancer is ongoing. In the present study, we investigated the anticancer effects of APR-246 in combination with conventional chemotherapy in primary cancer cells isolated from ascitic fluid from 10 ovarian, fallopian tube, or peritoneal cancer patients, 8 of which had HGS cancer. Cell viability was assessed with fluorometric microculture cytotoxicity assay (FMCA) and Combination Index was calculated using the Additive model. p53 status was determined by Sanger sequencing and single strand conformation analysis, and p53 protein expression by western blotting. We observed strong synergy with APR-246 and cisplatin in all tumor samples carrying a TP53 missense mutation, while synergistic or additive effects were found in cells with wild type or TP53 nonsense mutations. Strong synergy was also observed with carboplatin or doxorubicin. Moreover, APR-246 sensitized TP53 mutant primary ovarian cancer cells, isolated from a clinically platinum-resistant patient, to cisplatin; the IC50 value of cisplatin decreased 3.6 fold from 6.5 to 1.8 μM in the presence of clinically relevant concentration of APR-246. These results suggest that combination treatment with APR-246 and DNA-damaging drugs could significantly improve the treatment of patients with TP53 mutant HGS cancer, and thus provide strong support for the ongoing clinical study with APR-246 in combination with carboplatin and pegylated liposomal doxorubicin in patients with recurrent HGS cancer.