Reference Detail

Ref Type

Journal Article

PMID

(24504419)

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.

Journal	Vol	Issue	Date	Pages	Journal Short Title
PloS one	9	2	2014	e87220	PLoS One

URL

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.

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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
DS-7423	DS-7423	6	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
DS-7423		DS7423	mTOR Inhibitor 51 PI3K Inhibitor (Pan) 42	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, Nov 2023).

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
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 H1047R TP53 S90fs	ovarian clear cell adenocarcinoma	decreased response	DS-7423	Preclinical - Cell culture	Actionable	In a preclinical study, an ovarian clear cell adenocarcinoma cell line harboring PIK3CA H1047R and TP53 S90fs*33 demonstrated reduced sensitivity to DS-7423 in culture (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
TP53 R175H	ovarian clear cell adenocarcinoma	decreased response	DS-7423	Preclinical - Cell culture	Actionable	In a preclinical study, an ovarian clear cell adenocarcinoma cell line harboring TP53 R175H demonstrated reduced sensitivity to DS-7423 in culture (PMID: 24504419).	24504419
TP53 mutant	ovarian clear cell adenocarcinoma	decreased response	DS-7423	Preclinical	Actionable	In a preclinical study, ovarian clear cell adenocarcinoma cell lines harboring TP53 mutations demonstrated reduced sensitivity to DS-7423 induced apoptosis in culture compared to TP53 wild-type cells (PMID: 24504419).	24504419
TP53 S241F	ovarian clear cell adenocarcinoma	decreased response	DS-7423	Preclinical - Cell culture	Actionable	In a preclinical study, an ovarian clear cell adenocarcinoma cell line harboring TP53 S241F demonstrated reduced sensitivity to DS-7423 in culture (PMID: 24504419).	24504419