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Ref Type Journal Article
PMID (27179933)
Authors Fransson Å, Glaessgen D, Alfredsson J, Wiman KG, Bajalica-Lagercrantz S, Mohell N
Title Strong synergy with APR-246 and DNA-damaging drugs in primary cancer cells from patients with TP53 mutant High-Grade Serous ovarian cancer.
Journal Journal of ovarian research
Vol 9
Issue 1
Date 2016 May 14
URL
Abstract Text 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
TP53 L111Q missense unknown TP53 L111Q lies within the DNA-binding domain of the Tp53 protein (PMID: 22713868). L111Q has been identified in the scientific literature (PMID: 27179933, PMID: 25471132, PMID: 29386642), but has not been biochemically characterized and therefore, its effect on Tp53 protein function is unknown (PubMed, Jun 2022).
TP53 Y163H missense unknown TP53 Y163H lies within the DNA-binding domain of the Tp53 protein (PMID: 22713868). Y163H has been identified in the scientific literature (PMID: 27179933, PMID: 17764544, PMID: 28245875), but has not been biochemically characterized and therefore, its effect on Tp53 protein function is unknown (PubMed, Nov 2022).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
TP53 L111Q ovarian cancer sensitive APR-246 + Cisplatin Preclinical - Patient cell culture Actionable In a preclinical study, the combination of APR-246 and Platinol (cisplatin) resulted in strong synergism, thereby reducing cell viability in patient derived ovarian cancer cells harboring TP53 L111Q in culture (PMID: 27179933). 27179933
TP53 P278R ovarian cancer sensitive APR-246 + Cisplatin Preclinical - Patient cell culture Actionable In a preclinical study, the combination of APR-246 and Platinol (cisplatin) resulted in strong synergism, thereby reducing cell viability in patient derived ovarian cancer cells harboring TP53 P278R in culture (PMID: 27179933). 27179933
TP53 C238F fallopian tube cancer sensitive APR-246 + Cisplatin Preclinical - Patient cell culture Actionable In a preclinical study, the combination of APR-246 and Platinol (cisplatin) resulted in strong synergism, thereby reducing cell viability in patient derived fallopian tube cancer cells harboring TP53 C238F in culture (PMID: 27179933). 27179933
TP53 C135Y peritoneum cancer sensitive APR-246 + Cisplatin Preclinical - Patient cell culture Actionable In a preclinical study, the combination of APR-246 and Platinol (cisplatin) resulted in strong synergism, thereby reducing cell viability in patient derived peritoneum cancer cells harboring TP53 C135Y in culture (PMID: 27179933). 27179933
TP53 R280K ovarian cancer sensitive APR-246 + Cisplatin Preclinical - Patient cell culture Actionable In a preclinical study, the combination of APR-246 and Platinol (cisplatin) worked synergistically in culture, resulting in reduced cell viability in patient derived ovarian cancer cells harboring TP53 R280K (PMID: 27179933). 27179933
TP53 Y163H ovarian cancer sensitive APR-246 + Cisplatin Preclinical - Patient cell culture Actionable In a preclinical study, the combination of APR-246 and Platinol (cisplatin) resulted in strong synergism, thereby reducing cell viability in patient derived ovarian cancer cells harboring TP53 Y163H in culture (PMID: 27179933). 27179933
TP53 P151H ovarian cancer sensitive APR-246 + Cisplatin Preclinical - Patient cell culture Actionable In a preclinical study, the combination of APR-246 and Platinol (cisplatin) resulted in strong synergism, thereby reducing cell viability in patient derived ovarian cancer cells harboring TP53 P151H in culture (PMID: 27179933). 27179933