Genotype-Dependent Efficacy of a Dual PI3K/mTOR Inhibitor, NVP-BEZ235, and an mTOR Inhibitor, RAD001, in Endometrial Carcinomas

Shoji, Keiko; Oda, Katsutoshi; Kashiyama, Tomoko; Ikeda, Yuji; Nakagawa, Shunsuke; Sone, Kenbun; Miyamoto, Yukio; Hiraike, Haruko; Tanikawa, Michihiro; Miyasaka, Aki; Koso, Takahiro; Matsumoto, Yōko; Wada-Hiraike, Osamu; Kawana, Kei; Kuramoto, Hiroyuki; McCormick, Frank; Aburatani, Hiroyuki; Yano, Tetsu; Kozuma, Shiro; Taketani, Yuji

doi:10.1371/journal.pone.0037431

Cited by 69 publications

(51 citation statements)

References 44 publications

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“…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).…”

Section: Clinical Application Of the Results From Genomic Analysismentioning

confidence: 99%

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

et al. 2017

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Section: Clinical Application Of the Results From Genomic Analysismentioning

confidence: 99%

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

et al. 2017

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“…rapamycin analogs). It is known that NVP-BEZ235 displays significant antitumor activities in glioblastoma, lung, breast, renal cell and uterine endometrial carcinomas (12,14,13,27).…”

Section: Discussionmentioning

confidence: 99%

The PI3K/mTOR dual inhibitor NVP-BEZ235 reduces the growth of ovarian clear cell carcinoma

et al. 2014

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Abstract.Patients with clear cell carcinoma of the ovary (OCCC) have poor survival due to resistance to standard chemotherapy. OCCC has frequent activating mutations of the PIK3CA gene. The present study was conducted to clarify the efficacy of the inhibition of the PI3K-AKT-mTOR pathway in OCCC. We used 8 OCCC cell lines and 5 ovarian serous adenocarcinoma (OSAC) cell lines. The mutation status of the PIK3CA and KRAS genes was examined by direct sequencing. The IC 50 values of NVP-BEZ235 (BEZ235) and temsirolimus were determined by WST-8 assay. Protein expression levels of PI3K-AKT-mTOR pathway molecules were examined by western blotting. Cell cycle distribution was analyzed by flow cytometry. Annexin V staining was used for detecting apoptosis. We also investigated the effects of BEZ235 on OCCC tumor growth in a nude mouse xenograft model. Four of the 8 OCCC cell lines showed a PIK3CA mutation while none of the 5 OSAC cell lines showed a mutation. The IC 50 values of BEZ235 for the OCCC cell lines were lower than these values for the OSAC cell lines. The IC 50 value of temsirolimus was higher than BEZ235 in the OCCC cell lines. The PIK3CA mutation was more frequently noted in OCCC than OSAC cells, but the sensitivity of these cell lines to BEZ235 or temsirolimus was not related to the mutation status. pHER3 and pAkt proteins were expressed more frequently in OCCC compared with OSAC. However, protein expression levels were distributed widely, and were not related to the sensitivity. Treatment with BEZ235 suppressed expression of pAkt, although treatment with temsirolimus did not. OCCC cells exhibited G 1 phase arrest after treatment with BEZ235 and apoptosis with a higher concentration of the agent. BEZ235 significantly inhibited tumor growth in mice bearing OVISE and TU-OC-1 cell tumors. The present study indicated that the PI3K-AKT-mTOR pathway is a potential target for OCCC, and that BEZ235 warrants investigation as a therapeutic agent. IntroductionClear cell carcinoma of the ovary (OCCC) is recognized in the World Health Organization classification of ovarian tumors as a distinct histological entity. Its clinical behavior is distinctly different from other epithelial ovarian cancers (1). OCCC accounts for 3.7-12.1% of epithelial ovarian cancers (2,3). We found that response rates for platinum-based chemotherapy were 11.1% for OCCC and 72.5% for serous adenocarcinoma (SAC), suggesting that OCCC resists conventional platinumbased chemotherapy (4). A novel therapeutic strategy is needed to improve the prognosis of patients with OCCC.PIK3CA is located at the 3q26.3 locus and encodes the catalytic subunit of the phosphatidylinositol 3-kinase (PI3K), p110α (5). In response to an extracellular signal, the activated p110α phosphorylates PIP2 to generate PIP3. The PIP3 recruits AKT to the plasma membrane, where it is phosphorylated and activated by phosphatidylinositol-dependent kinase 1 (PDK1) and PDK2. Activated AKT can directly activate the mammalian target of rapamycin (mTOR) by phosphorylation at Ser2448. mTOR ...

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“…Dysregulation of the PI3K/Akt pathway has been observed in all subtypes of EC and associated with more aggressive disease . Furthermore, PI3K and mTOR inhibitors are in phase I/II trials in advanced EC based on molecular alterations reported in aggressive ECs (Salvesen et al 2012, Shoji et al 2012.…”

Section: Cell Signaling Pathwaysmentioning

confidence: 99%

Tumor progression, metastasis, and modulators of epithelial–mesenchymal transition in endometrioid endometrial carcinoma: an update

Makker

Goel

2015

Endocrine-Related Cancer

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Endometrioid endometrial carcinoma (EEC), also known as type 1 endometrial cancer (EC), accounts for over 70-80% of all cases that are usually associated with estrogen stimulation and often develops in a background of atypical endometrial hyperplasia. The increased incidence of EC is mainly confined to this type of cancer. Most EEC patients present at an early stage and generally have a favorable prognosis; however, up to 30% of EEC present as high risk tumors, which have invaded deep into the myometrium at diagnosis and progressively lead to local or extra pelvic metastasis. The poor survival of advanced EC is related to the lack of effective therapies, which can be attributed to poor understanding of the molecular mechanisms underlying the progression of disease toward invasion and metastasis. Multiple lines of evidence illustrate that epithelial-mesenchymal transition (EMT)-like events are central to tumor progression and malignant transformation, endowing the incipient cancer cell with invasive and metastatic properties. The aim of this review is to summarize the current knowledge on molecular events associated with EMT in progression, invasion, and metastasis of EEC. Further, the role of epigenetic modifications and microRNA regulation, tumor microenvironment, and microcystic elongated and fragmented glands like invasion pattern have been discussed. We believe this article may perhaps stimulate further research in this field that may aid in identifying high risk patients within this clinically challenging patient group and also lead to the recognition of novel targets for the prevention of metastasis -the most fatal consequence of endometrial carcinogenesis.

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Genotype-Dependent Efficacy of a Dual PI3K/mTOR Inhibitor, NVP-BEZ235, and an mTOR Inhibitor, RAD001, in Endometrial Carcinomas

Cited by 69 publications

References 44 publications

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

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

The PI3K/mTOR dual inhibitor NVP-BEZ235 reduces the growth of ovarian clear cell carcinoma

Tumor progression, metastasis, and modulators of epithelial–mesenchymal transition in endometrioid endometrial carcinoma: an update

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