Reference Detail

Ref Type

Journal Article

PMID

(26086967)

Authors

Mohell N, Alfredsson J, Fransson A, Uustalu M, Bystrom S, Gullbo J, Hallberg A, Bykov VJ, Bjorklund U, Wiman KG

Title

APR-246 overcomes resistance to cisplatin and doxorubicin in ovarian cancer cells.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cell death & disease	6		2015	e1794	Cell Death Dis

URL

Abstract Text

Two main causes of platinum resistance are mutation in the tumor suppressor gene TP53 and drug-induced increase in intracellular glutathione concentration. Mutations in TP53 occur in about 50% of human tumors. APR-246 (PRIMA-1(MET)) is the first clinical-stage compound that reactivates mutant p53 and induces apoptosis. APR-246 is a prodrug that is converted to the active compound methylene quinuclidinone (MQ), a Michael acceptor that binds to cysteine residues in mutant p53 and restores its wild-type conformation. Here, we show that MQ also binds to cysteine in glutathione, thus decreasing intracellular free glutathione concentration. We also show that treatment with APR-246 completely restores the cisplatin and doxorubicin sensitivity to p53-mutant drug-resistant ovarian cancer cells. We propose that this unique ability of APR-246/MQ to bind to cysteines in both mutant p53 and glutathione has a key role in the resensitization as well as in the outstanding synergistic effects observed with APR-246 in combination with platinum compounds in ovarian cancer cell lines and primary cancer cells. However, MQ binding to cysteines in other targets, for example, thioredoxin reductase, may contribute as well. Strong synergy was also observed with the DNA-damaging drugs doxorubicin and gemcitabine, while additive effects were found with the taxane docetaxel. Our results provide a strong rationale for the ongoing clinical study with APR-246 in combination with platinum-based therapy in patients with p53-mutant recurrent high-grade serous (HGS) ovarian cancer. More than 96% of these patients carry TP53 mutations. Combined treatment with APR-246 and platinum or other DNA-damaging drugs could allow dramatically improved therapy of a wide range of therapy refractory p53 mutant tumors.

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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

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
TP53 Y163C	lung small cell carcinoma	sensitive	APR-246 + Cisplatin	Preclinical	Actionable	In a preclinical study, the combination of APR-246 and Platinol (cisplatin) worked synergistically to inhibit growth of small lung cancer cells harboring TP53 Y163C in culture (PMID: 26086967).	26086967
TP53 R248W	lung non-small cell carcinoma	sensitive	APR-246 + Cisplatin	Preclinical	Actionable	In a preclinical study, the combination of APR-246 and Platinol (cisplatin) worked synergistically to inhibit growth of non-small lung cancer cells harboring TP53 R248W in culture (PMID: 26086967).	26086967
TP53 R273H	lung non-small cell carcinoma	sensitive	APR-246 + Cisplatin	Preclinical	Actionable	In a preclinical study, the combination of APR-246 and Platinol (cisplatin) worked synergistically to inhibit growth of non-small lung cancer cells harboring TP53 R273H in culture (PMID: 26086967).	26086967
TP53 R248Q	ovarian cancer	sensitive	APR-246 + Cisplatin	Preclinical	Actionable	In a preclinical study, the combination of APR-246 and Platinol (cisplatin) worked synergistically to inhibit growth of a Platinol (cisplatin)-resistant ovarian cancer cell line harboring TP53 R248Q in culture and inhibited tumor growth in TP53 R248Q-carrying ovarian cancer cell line xenograft models (PMID: 26086967).	26086967