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|Ref Type||Journal Article|
|Authors||Kashiyama T, Oda K, Ikeda Y, Shiose Y, Hirota Y, Inaba K, Makii C, Kurikawa R, Miyasaka A, Koso T, Fukuda T, Tanikawa M, Shoji K, Sone K, Arimoto T, Wada-Hiraike O, Kawana K, Nakagawa S, Matsuda K, McCormick F, Aburatani H, Yano T, Osuga Y, Fujii T|
|Title||Antitumor activity and induction of TP53-dependent apoptosis toward ovarian clear cell adenocarcinoma by the dual PI3K/mTOR inhibitor DS-7423.|
|Abstract Text||DS-7423, a novel, small-molecule dual inhibitor of phosphatidylinositol-3-kinase (PI3K) and mammalian target of rapamycin (mTOR), is currently in phase I clinical trials for solid tumors. Although DS-7423 potently inhibits PI3Kα (IC50 = 15.6 nM) and mTOR (IC50 = 34.9 nM), it also inhibits other isoforms of class I PI3K (IC50 values: PI3Kβ = 1,143 nM; PI3Kγ = 249 nM; PI3Kδ = 262 nM). The PI3K/mTOR pathway is frequently activated in ovarian clear cell adenocarcinomas (OCCA) through various mutations that activate PI3K-AKT signaling. Here, we describe the anti-tumor effect of DS-7423 on a panel of nine OCCA cell lines. IC50 values for DS-7423 were <75 nM in all the lines, regardless of the mutational status of PIK3CA. In mouse xenograft models, DS-7423 suppressed the tumor growth of OCCA in a dose-dependent manner. Flow cytometry analysis revealed a decrease in S-phase cell populations in all the cell lines and an increase in sub-G1 cell populations following treatment with DS-7423 in six of the nine OCCA cell lines tested. DS-7423-mediated apoptosis was induced more effectively in the six cell lines without TP53 mutations than in the three cell lines with TP53 mutations. Concomitantly with the decreased phosphorylation level of MDM2 (mouse double minute 2 homolog), the level of phosphorylation of TP53 at Ser46 was increased by DS-7423 in the six cell lines with wild-type TP53, with induction of genes that mediate TP53-dependent apoptosis, including p53AIP1 and PUMA at 39 nM or higher doses. Our data suggest that the dual PI3K/mTOR inhibitor DS-7423 may constitute a promising molecular targeted therapy for OCCA, and that its antitumor effect might be partly obtained by induction of TP53-dependent apoptosis in TP53 wild-type OCCAs.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|DS-7423||DS7423||mTOR Inhibitor 51 PI3K Inhibitor (Pan) 38||DS-7423 inhibits both PI3K kinase and mTORC1/2, which may result in tumor cell apoptosis and suppression of tumor growth (PMID: 24504419).|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|PIK3CA||E545V||missense||unknown||PIK3CA E545V is a hotspot mutation that lies within the PIK helical domain of the Pik3ca protein (UniProt.org). E545V has been identified in sequencing studies (PMID: 29482551, PMID: 24504419), but has not been biochemically characterized and therefore, its effect on Pik3ca protein function is unknown (PubMed, May 2020).|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|Unknown unknown||ovarian clear cell adenocarcinoma||not applicable||DS-7423||Preclinical - Cell line xenograft||Actionable||In a preclinical study, DS-7423 inhibited proliferation of ovarian clear cell adenocarcinoma cell lines in culture and suppressed tumor growth in cell line xenograft animal models (PMID: 24504419).||24504419|
|PIK3CA E545V||ovarian clear cell adenocarcinoma||sensitive||DS-7423||Preclinical - Cell culture||Actionable||In a preclinical study, an ovarian clear cell adenocarcinoma cell line harboring PIK3CA E545V was sensitive to DS-7423 in culture, demonstrating inhibition of cell proliferation (PMID: 24504419).||24504419|
|PIK3CA C420R||ovarian clear cell adenocarcinoma||sensitive||DS-7423||Preclinical - Cell culture||Actionable||In a preclinical study, an ovarian clear cell adenocarcinoma cell line harboring PIK3CA C420R was sensitive to DS-7423 in culture, demonstrating inhibition of cell proliferation (PMID: 24504419).||24504419|