Antitumor Activity and Induction of TP53-Dependent Apoptosis toward Ovarian Clear Cell Adenocarcinoma by the Dual PI3K/mTOR Inhibitor DS-7423

Abstract

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.

Genome-wide analysis of gynecologic cancer: The Cancer Genome Atlas in ovarian and endometrial cancer

“…A molecular-targeted drug may only inhibit one signaling pathway and thus, conventional chemotherapy may be required to obtain a good therapeutic effect (92). Trials of novel drugs that are able to simultaneously inhibit PI3K and mTOR have also been conducted (93,94). These include a phase I study on the use of DS-7423 for the treatment of ovarian cancer and a phase I study on the use of NVP-BEZ235 for the treatment of endometrial cancer, in which, the efficacy of NVP-BEZ235 was compared with that of everolimus (94).…”

Judicious Toggling of mTOR Activity to Combat Insulin Resistance and Cancer: Current Evidence and Perspectives

“…At present, at least 10 dual PI3K-mTOR inhibitors are in various stages of preclinical or/and clinical testing (Table 3) (Maira et al, 2008; Park et al, 2008; Schnell et al, 2008; Serra et al, 2008; Brachmann et al, 2009; Cao et al, 2009; Guillard et al, 2009; Liu et al, 2009, 2015; Marone et al, 2009; McMillin et al, 2009; Cho et al, 2010; Dolly et al, 2010; Knight et al, 2010; Mallon et al, 2010, 2011; Wagner et al, 2011; Wallin et al, 2011; Yuan et al, 2011; Mahadevan et al, 2012; Markman et al, 2012; Wang F.-Z. et al, 2013; Britten et al, 2014; Hong et al, 2014; Kashiyama et al, 2014; Makker et al, 2014; Papadopoulos et al, 2014, 2015; Powles et al, 2014; Yokota et al, 2014; Yu et al, 2014; Salazar et al, 2015; Bendell et al, 2015b; Chen et al, 2016; Gravina et al, 2016; Munster et al, 2016; Seront et al, 2016; Thijssen et al, 2016). …”

“…These effects were in turn translated to G1 cell cycle arrest (Yuan et al, 2011; Wang F.-Z. et al, 2013; Kashiyama et al, 2014; Yu et al, 2014; Chen et al, 2016) or/and apoptosis induction (Park et al, 2008; Brachmann et al, 2009; McMillin et al, 2009; Cho et al, 2010; Mallon et al, 2010; Wallin et al, 2011; Wang F.-Z. et al, 2013; Kashiyama et al, 2014).…”

Antitumor activity of a combination of dual PI3K/mTOR inhibitor SAR245409 and selective MEK1/2 inhibitor pimasertib in endometrial carcinomas

“…The preclinical pharmacological characterization of SAR245409 and pimasertib (molecular structure, biochemical, cellular, and in vivo data) has been described previously [29,30]. SAR245409 inhibits mTOR signaling in both PI3K-dependent and PI3K-independent manner, which results in suppression of mTOR signaling at lower doses than PI3K/AKT signaling [29] as reported for other dual PI3K/mTOR inhibitors [12,31]. Both agents are orally bioavailable small-molecule inhibitors and have been under phase I/II clinical trials for some malignant tumors.…”