sirolimus and Adenocarcinoma--Clear-Cell

Hypoxia-inducible factor-1 (HIF-1) is one of the most promising pharmacological targets for all types of cancer, including ovarian cancer. Ovarian clear cell carcinoma (OCCC) has poor prognosis because of its insensitivity to chemotherapy. To elucidate the characteristics of this troublesome cancer, we examined HIF-1α expression under normoxia or hypoxia in various ovarian cancer cell lines. HIF-1α was highly expressed under normoxia only in RMG-1, an OCCC cell line. To examine whether HIF-1 is involved in the tumorigenesis of RMG-1 cells, we established HIF-1α-silenced cells, RMG-1HKD. The proliferation rate of RMG-1HKD cells was faster than that of RMG-1 cells. Furthermore, the activity of MEK/ERK in the Ras pathway increased in RMG-1HKD cells, whereas that of mTOR in the PI3K pathway did not change. Activation of the Ras pathway was attributable to the increase in phosphorylated MEK via PP2A inactivation. To confirm the crosstalk between the PI3K and Ras pathways in vivo, RMG-1 or RMG-1HKD cells were transplanted into the skin of nude mice with rapamycin (an inhibitor of mTOR), PD98059 (an inhibitor of MEK), or both. RMG-1HKD cells showed higher sensitivity to PD98059 than that observed in RMD-1 cells, whereas the combination therapy resulted in synergistic inhibition of both cells. These findings suggest that inhibition of HIF-1, a downstream target of mTOR in the PI3K pathway, activates the Ras pathway on account of the increase in MEK phosphorylation via PP2A inactivation, and the crosstalk between the 2 pathways could be applied in the combination therapy for HIF-1-overexpressing cancers such as OCCC.

Topics: Adenocarcinoma, Clear Cell; Animals; Cell Line, Tumor; Cell Proliferation; Disease Models, Animal; Female; Gene Expression Regulation, Neoplastic; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Mice; Mitogen-Activated Protein Kinases; Ovarian Neoplasms; Oxygen Consumption; Phosphatidylinositol 3-Kinases; Phosphorylation; Protein Binding; Protein Kinase Inhibitors; Protein Phosphatase 2; Proto-Oncogene Proteins p21(ras); Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

The SCAN gynaecological cancers systemic therapy workgroup aimed to develop Singapore Cancer Network (SCAN) clinical practice guidelines for the systemic therapy of endometrial (uterine) cancer.. The workgroup utilised a modified ADAPTE process to calibrate high quality international evidence-based clinical practice guidelines to our local setting.. Three international guidelines were evaluated- those developed by the National Cancer Comprehensive Network (2015), the European Society of Medical Oncology (2013) and the Cancer Council Australia (2011). Recommendations on the role of chemotherapy following surgery in women diagnosed with endometrial cancer, the chemotherapeutic options for women with advanced or recurrent endometrial cancers and the role of chemotherapy in women with uterine papillary serous carcinoma or clear cell carcinoma were developed.. These adapted guidelines form the SCAN Guidelines 2015 for the systemic therapy of endometrial (uterine) cancer.

Topics: Adenocarcinoma, Clear Cell; Antineoplastic Combined Chemotherapy Protocols; Aromatase Inhibitors; Carboplatin; Carcinoma, Endometrioid; Chemotherapy, Adjuvant; Cisplatin; Endometrial Neoplasms; Female; Humans; Hysterectomy; Neoplasm Recurrence, Local; Neoplasms, Cystic, Mucinous, and Serous; Paclitaxel; Progestins; Singapore; Sirolimus; Tamoxifen

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.

Topics: Adenocarcinoma, Clear Cell; Animals; Antineoplastic Agents; Apoptosis; Apoptosis Regulatory Proteins; Cell Line, Tumor; Cell Proliferation; Class I Phosphatidylinositol 3-Kinases; DNA Mutational Analysis; Female; Flow Cytometry; Gene Expression Regulation, Neoplastic; Humans; Mice, Nude; Ovarian Neoplasms; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Phosphorylation; Phosphoserine; Protein Kinase Inhibitors; RNA, Messenger; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Tumor Suppressor Protein p53; Xenograft Model Antitumor Assays

The objective of this study was to investigate the chemotherapeutic agents that produce the strongest synergistic effects when combined with trabectedin against ovarian clear cell carcinoma (CCC), which is regarded as an aggressive chemoresistant histological subtype.. Using 4 human CCC cell lines (RMG1, RMG2, KOC7C, and HAC2), the cytotoxicities of trabectedin, SN-38, topotecan, doxorubicin, cisplatin, and paclitaxel as single agents were first assessed using the MTS assay. Then, the cytotoxicities of combination treatments involving trabectedin and 1 of the other 4 agents were evaluated by isobologram analysis to examine whether these combinations displayed synergistic, additive, or antagonistic effects. The antitumor activities of the combination treatments were also examined using cisplatin-resistant and paclitaxel-resistant CCC sublines, which were derived from the parental CCC cells by continuously exposing them to cisplatin or paclitaxel. Finally, we determined the effect of everolimus on the antitumor efficacy of trabectedin-based combination chemotherapy.. Concurrent exposure to trabectedin and SN-38 or topotecan resulted in synergistic interactions in all 4 CCC cell lines. Among the tested combinations, trabectedin plus SN-38 was the most effective cytotoxic regimen. The combination of trabectedin plus SN-38 also had strong synergistic effects on both the cisplatin-resistant and paclitaxel-resistant CCC cell lines. Treatment with everolimus significantly enhanced the antitumor activity of trabectedin plus SN-38 or topotecan.. Combination treatment with trabectedin and SN-38 displays the greatest cytotoxic effect against ovarian CCC. Our in vitro study provides the rationale for future clinical trials of trabectedin plus irinotecan with or without everolimus in patients with ovarian CCC in both the front-line chemotherapy setting and as a second-line treatment of recurrent CCC that had previously been treated with cisplatin or paclitaxel.

Topics: Adenocarcinoma, Clear Cell; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Blotting, Western; Camptothecin; Cell Proliferation; Cisplatin; Dioxoles; Doxorubicin; Drug Resistance, Neoplasm; Drug Synergism; Everolimus; Female; Humans; Irinotecan; Ovarian Neoplasms; Paclitaxel; Sirolimus; Tetrahydroisoquinolines; Topotecan; Trabectedin; Tumor Cells, Cultured

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 IC50 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 IC50 values of BEZ235 for the OCCC cell lines were lower than these values for the OSAC cell lines. The IC50 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 G1 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.

Topics: Adenocarcinoma, Clear Cell; Animals; Cell Line, Tumor; Cystadenoma, Serous; Female; Gene Expression Regulation, Neoplastic; Humans; Imidazoles; Mice; Mice, Nude; Neoplasms, Experimental; Ovarian Neoplasms; Phosphoinositide-3 Kinase Inhibitors; Quinolines; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Xenograft Model Antitumor Assays

The goal of this study was to examine the role of mTOR complex 2 (mTORC2) as a therapeutic target in ovarian clear cell carcinoma (CCC), which is regarded as an aggressive, chemoresistant histologic subtype. Using tissue microarrays of 98 primary ovarian cancers [52 CCCs and 46 serous adenocarcinomas (SAC)], activation of mTORC2 was assessed by immunohistochemistry. Then, the growth-inhibitory effect of mTORC2-targeting therapy, as well as the role of mTORC2 signaling as a mechanism for acquired resistance to the mTOR complex 1 (mTORC1) inhibitor RAD001 in ovarian CCC, were examined using two pairs of RAD001-sensitive parental (RMG2 and HAC2) and RAD001-resistant CCC cell lines (RMG2-RR and HAC2-RR). mTORC2 was more frequently activated in CCCs than in SACs (71.2% vs. 45.7%). Simultaneous inhibition of mTORC1 and mTORC2 by AZD8055 markedly inhibited the proliferation of both RAD001-sensitive and -resistant cells in vitro. Treatment with RAD001 induced mTORC2-mediated AKT activation in RAD001-sensitive CCC cells. Moreover, increased activation of mTORC2-AKT signaling was observed in RAD001-resistant CCC cells compared with the respective parental cells. Inhibition of mTORC2 during RAD001 treatment enhanced the antitumor effect of RAD001 and prevented CCC cells from acquiring resistance to RAD001. In conclusion, mTORC2 is frequently activated, and can be a promising therapeutic target, in ovarian CCCs. Moreover, mTORC2-targeted therapy may be efficacious in a first-line setting as well as for second-line treatment of recurrent disease developing after RAD001-treatment.

Topics: Adenocarcinoma, Clear Cell; Animals; Apoptosis; Cell Line, Tumor; Cell Proliferation; Everolimus; Female; Humans; Mechanistic Target of Rapamycin Complex 2; Mice; Mice, Nude; Multiprotein Complexes; Ovarian Neoplasms; RNA, Small Interfering; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

Before setting into the clinical trial using a combination of mammalian target of rapamycin (mTOR) inhibitors (rapamycin and everolimus) and other anticancer drugs, this study was conducted to confirm the efficacy of the new therapeutic strategy for ovarian clear cell adenocarcinoma (CCA), which targeted mTOR-hypoxia-induced factor (HIF) signal transduction system.. Using the cultured cells of CCA and animal models, alteration of mTOR-HIF cofactors and cell proliferation under the mTOR inhibitor-treated condition were analyzed.. Mammalian target of rapamycin-HIF cofactors were inhibited dependent on concentration by mTOR inhibitor, resulting in suppression of the cultured CCA proliferation. However, von Hippel-Lindau was up-regulated at the messenger RNA level. In the nude mice with subcutaneously implanted CCA cells, apoptosis and necrosis were detected especially around the center of the tumors in the mTOR inhibitor-treated group more conspicuously than in the nontreated group. In the assessment of combination therapy with other antitumor agents, a combined treatment with mTOR inhibitor and chemotherapeutic agents caused a significant decrease in tumor size compared to the chemotherapeutic agents-only group.. Treatment by mTOR inhibitor is expected to down-regulate the cell proliferation of the CCA as a new therapeutic strategy.

Topics: Adenocarcinoma, Clear Cell; Animals; Antibiotics, Antineoplastic; Apoptosis; Blotting, Western; Cell Proliferation; Drug Therapy, Combination; Everolimus; Female; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Immunoenzyme Techniques; Immunosuppressive Agents; In Vitro Techniques; Mice; Mice, Inbred BALB C; Mice, Nude; Oncogene Protein v-akt; Ovarian Neoplasms; Prognosis; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Signal Transduction; Sirolimus; Survival Rate; TOR Serine-Threonine Kinases; Tumor Cells, Cultured; Von Hippel-Lindau Tumor Suppressor Protein; Xenograft Model Antitumor Assays

A 63-year-old man presenting with a 7.2-cm right renal mass, an inferior vena cava tumor thrombus, and pulmonary metastases underwent renal mass biopsy that revealed clear cell renal cell carcinoma. Temsirolimus (25 mg weekly) was given because of the extent of the disease and poor performance status, which resulted in a marked reduction in the tumor thrombus (from level III to level I) after 20 weeks of treatment. Subsequently, radical nephrectomy and tumor thrombectomy were carried out. Final pathological analysis confirmed the diagnosis of high-grade clear cell carcinoma (pT4N0M1). One year after initiation of temsirolimus therapy, the patient remained alive despite the presence of disease.

Topics: Adenocarcinoma, Clear Cell; Antineoplastic Agents; Carcinoma, Renal Cell; Humans; Kidney Neoplasms; Male; Middle Aged; Neoadjuvant Therapy; Neoplasm Staging; Sirolimus; Thrombosis; Vena Cava, Inferior

Clear cell carcinoma (CCC) of the ovary is well-known to be chemotherapy resistant compared with other histologic subtypes. An inhibitor against the mammalian target of rapamycin, temsirolimus (TEM) has been reported to be effective in renal CCC. Therefore, we investigated the effects of TEM in patients with CCC of the ovary. Six patients with CCC of the ovary who had been heavily pretreated by more than 4 regimens were given TEM: the cycle consisted of weekly TEM (10 mg/m(2)) for 3 weeks followed by 1 week off. The treatment was continued until development of either progressive disease, or unmanageable adverse effects. Response evaluation was based upon the Response Evaluation Criteria in Solid Tumors version 1.0. Adverse effects were analyzed according to Common Terminology Criteria for Adverse Events version 3.0. The median cycle of weekly TEM was 3 (range 2-14). Among five cases in which responses could be evaluated, partial response was observed in one case (20%) and stabilized disease was seen in another case (20%). There were no toxicities greater than grade 3, and no case developed severe toxicity requiring discontinuation of weekly TEM. The patient who showed a partial response obtained a progression-free period of 14 months. In conclusion, weekly TEM shows a potential therapeutic benefit for patients with CCC of the ovary. Further studies including a translational approach are needed to select candidates for whom TEM therapy would be beneficial.

Topics: Adenocarcinoma, Clear Cell; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; CA-125 Antigen; Drug Administration Schedule; Female; Humans; Middle Aged; Neoplasm Staging; Ovarian Neoplasms; Sirolimus

The objective of this study was to evaluate the antitumor efficacy of trabectedin in clear cell carcinoma (CCC) of the ovary, which is regarded as an aggressive, chemoresistant, histologic subtype.. Using 6 human ovarian cancer cell lines (3 CCC and 3 serous adenocarcinomas), the antitumor effects of trabectedin were examined in vitro, and we compared its activity according to histology. We next examined the antitumor activity of trabectedin in both cisplatin-resistant and paclitaxel-resistant CCC cells in vitro. Then, the in vivo effects of trabectedin were evaluated using mice inoculated with CCC cell lines. Using 2 pairs of trabectedin-sensitive parental and trabectedin-resistant CCC sublines, we investigated the role of mTOR in the mechanism of acquired resistance to trabectedin. Finally, we determined the effect of mTOR inhibition by everolimus on the antitumor efficacy of trabectedin in vitro and in vivo.. Trabectedin showed significant antitumor activity toward chemosensitive and chemoresistant CCC cells in vitro. Mouse xenografts of CCC cells revealed that trabectedin significantly inhibits tumor growth. Greater activation of mTOR was observed in trabectedin-resistant CCC cells than in their respective parental cells. The continuous inhibition of mTOR significantly enhanced the therapeutic efficacy of trabectedin and prevented CCC cells from acquiring resistance to trabectedin.. Trabectedin is a promising agent for CCC as a first-line chemotherapy and as a second-line treatment of recurrent CCC that had previously been treated with cisplatin or paclitaxel. Moreover, trabectedin combined with everolimus may be more efficacious for the management of CCC.

Topics: Adenocarcinoma, Clear Cell; Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Dioxoles; Drug Resistance, Neoplasm; Enzyme Activation; Everolimus; Female; Humans; Mice; Mice, Nude; Ovarian Neoplasms; Proto-Oncogene Proteins c-akt; Signal Transduction; Sirolimus; Tetrahydroisoquinolines; TOR Serine-Threonine Kinases; Trabectedin; Xenograft Model Antitumor Assays

MicroRNAs (miRNAs) are small noncoding RNAs that direct gene regulation through translational repression and degradation of complementary mRNA. Although miRNAs have been implicated as oncogenes and tumor suppressors in a variety of human cancers, functional roles for individual miRNAs have not been described in clear cell ovarian carcinoma, an aggressive and chemoresistant subtype of ovarian cancer. We performed deep sequencing to comprehensively profile miRNA expression in 10 human clear cell ovarian cancer cell lines compared with normal ovarian surface epithelial cultures and discovered 54 miRNAs that were aberrantly expressed. Because of the critical roles of the phosphatidylinositol 3-kinase/v-akt murine thymoma viral oncogene homolog 1/mammalian target of rapamycin (mTOR) pathway in clear cell ovarian cancer, we focused on mir-100, a putative tumor suppressor that was the most down-regulated miRNA in our cancer cell lines, and its up-regulated target, FRAP1/mTOR. Overexpression of mir-100 inhibited mTOR signaling and enhanced sensitivity to the rapamycin analog RAD001 (everolimus), confirming the key relationship between mir-100 and the mTOR pathway. Furthermore, overexpression of the putative tumor suppressor mir-22 repressed the EVI1 oncogene, which is known to suppress apoptosis by stimulating phosphatidylinositol 3-kinase/v-akt murine thymoma viral oncogene homolog 1 signaling. In addition to these specific effects, reversing the expression of mir-22 and the putative oncogene mir-182 had widespread effects on target and nontarget gene populations that ultimately caused a global shift in the cancer gene signature toward a more normal state. Our experiments have revealed strong candidate miRNAs and their target genes that may contribute to the pathogenesis of clear cell ovarian cancer, thereby highlighting alternative therapeutic strategies for the treatment of this deadly cancer.

Topics: Adenocarcinoma, Clear Cell; Cell Line, Tumor; Cell Survival; Cells, Cultured; Computational Biology; Dose-Response Relationship, Drug; Epithelial Cells; Everolimus; Female; Gene Expression Profiling; Gene Knockdown Techniques; Humans; Intracellular Signaling Peptides and Proteins; MicroRNAs; Oligonucleotide Array Sequence Analysis; Ovarian Neoplasms; Ovary; Protein Serine-Threonine Kinases; RNA, Messenger; Sequence Analysis, RNA; Sirolimus; TOR Serine-Threonine Kinases

Malignant tumors usually involve a relatively hypoxic state, which induces overexpression of hypoxia-inducible factor-1alpha (HIF-1alpha) to satisfactorily enable the tumor to survive. Thus, inhibition of the mammalian target of rapamycin (mTOR) pathway including HIF-1alpha is expected to play a major role in suppression of tumor cell growth, having recently drawn much attention as an anti-cancer therapeutic strategy for various malignant tumors. In the present study, which compared clear cell adenocarcinoma (CLA) of the ovary with serous adenocarcinoma (SEA), the immunohistochemical expression of mTOR, phosphorylated-mTOR (p-mTOR), HIF-1alpha, and vascular endothelial growth factor (VEGF) was examined in surgically resected specimens of 29 SEA and 47 CLA. There were no significant differences in expression of mTOR, HIF-1alpha and VEGF between SEA and CLA, but it was noted that p-mTOR expression was more prominent in CLA than SEA. Then, using the cell lines of CLA (RMG-1 and W3uF), an experimental study was designed to clarify whether tumor suppression due to downregulation of mTOR activity could represent a promising therapeutic strategy for CLA. After treatment of an analogue of rapamycin (everolimus), expression of mTOR, p-mTOR, HIF-1alpha and VEGF was examined on western blot. As a result, although mTOR expression remained unchangeable, expression of p-mTOR, HIF-1alpha and VEGF was shown to be sharply depressed. The same expression alterations were demonstrated in the xenograft model treated with everolimus. In conclusion, mTOR-targeted therapy through usage of drugs such as everolimus may be more effective for CLA of the ovary because of its significant expression of p-mTOR.

Topics: Adenocarcinoma, Clear Cell; Adult; Aged; Animals; Antibiotics, Antineoplastic; Blotting, Western; Cell Line, Tumor; Everolimus; Female; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Immunohistochemistry; Mice; Middle Aged; Ovarian Neoplasms; Protein Kinases; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Vascular Endothelial Growth Factor A; Xenograft Model Antitumor Assays

Mammalian target of rapamycin (mTOR) plays a central role in cell proliferation and is regarded as a promising target in cancer therapy, including for ovarian cancer. This study aimed to examine the role of mTOR as a therapeutic target in clear cell carcinoma of the ovary, which is regarded as an aggressive, chemoresistant histologic subtype.. Using tissue microarrays of 98 primary ovarian cancers (52 clear cell carcinomas and 46 serous adenocarcinomas), the expression of phospho-mTOR was assessed by immunohistochemistry. Then, the growth-inhibitory effect of mTOR inhibition by RAD001 (everolimus) was examined using two pairs of cisplatin-sensitive parental (RMG1 and KOC7C) and cisplatin-resistant human clear cell carcinoma cell lines (RMG1-CR and KOC7C-CR) both in vitro and in vivo.. Immunohistochemical analysis showed that mTOR was more frequently activated in clear cell carcinomas than in serous adenocarcinomas (86.6% versus 50%). Treatment with RAD001 markedly inhibited the growth of both RMG1 and KOC7C cells both in vitro and in vivo. Increased expression of phospho-mTOR was observed in cisplatin-resistant RMG1-CR and KOC7C-CR cells, compared with the respective parental cells. This increased expression of phospho-mTOR in cisplatin-resistant cells was associated with increased activation of AKT. RMG1-CR and KOC7C-CR cells showed greater sensitivity to RAD001 than did parental RMG1 and KOC7C cells, respectively, in vitro and in vivo.. mTOR is frequently activated in clear cell carcinoma and can be a promising therapeutic target in the management of clear cell carcinoma. Moreover, mTOR inhibition by RAD001 may be efficacious as a second-line treatment of recurrent disease in patients previously treated with cisplatin.

Topics: Adenocarcinoma, Clear Cell; Animals; Antineoplastic Agents; Cell Line, Tumor; Cisplatin; Drug Resistance, Neoplasm; Everolimus; Female; Humans; Immunosuppressive Agents; Mice; Mice, Nude; Ovarian Neoplasms; Protein Kinases; Proto-Oncogene Proteins c-akt; Sirolimus; Tissue Array Analysis; TOR Serine-Threonine Kinases; Xenograft Model Antitumor Assays