1. Role of YAP1 as a Marker of Sensitivity to Dual AKT and P70S6K Inhibition in Ovarian and Uterine Malignancies
- Author
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Kshipra M. Gharpure, Cristina Ivan, Anil K. Sood, Sarah L. Linesch, Kyunghee Noh, Jie Huang, Rebecca A. Previs, Monika Haemmerle, Rajesha Rupaimoole, Lingegowda S. Mangala, Michael J. Wagner, Michael McGuire, Guillermo N. Armaiz-Pena, Sunila Pradeep, Heather J. Dalton, Sherry Y. Wu, Archana S. Nagaraja, Yasmin A. Lyons, Piotr L. Dorniak, Justyna Filant, and Jean M. Hansen
- Subjects
0301 basic medicine ,Oncology ,Cancer Research ,Angiogenesis ,Uterus ,AKT1 ,Angiogenesis Inhibitors ,Apoptosis ,Kaplan-Meier Estimate ,chemistry.chemical_compound ,0302 clinical medicine ,Antineoplastic Combined Chemotherapy Protocols ,Ovarian Neoplasms ,Ribosomal Protein S6 Kinases, 70-kDa ,Articles ,Tumor Burden ,Bevacizumab ,medicine.anatomical_structure ,Paclitaxel ,030220 oncology & carcinogenesis ,Uterine Neoplasms ,Female ,medicine.drug ,medicine.medical_specialty ,Mice, Nude ,Biology ,Inhibitory Concentration 50 ,03 medical and health sciences ,Uterine cancer ,Cell Line, Tumor ,Internal medicine ,Biomarkers, Tumor ,medicine ,Animals ,Humans ,Protein Kinase Inhibitors ,Adaptor Proteins, Signal Transducing ,Cell Proliferation ,Cancer ,YAP-Signaling Proteins ,Phosphoproteins ,medicine.disease ,Antineoplastic Agents, Phytogenic ,Xenograft Model Antitumor Assays ,030104 developmental biology ,Endocrinology ,chemistry ,Ovarian cancer ,Proto-Oncogene Proteins c-akt ,Transcription Factors - Abstract
Background The PI3K/AKT/P70S6K pathway is an attractive therapeutic target in ovarian and uterine malignancies because of its high rate of deregulation and key roles in tumor growth. Here, we examined the biological effects of MSC2363318A, which is a novel inhibitor of AKT1, AKT3, and P70S6K. Methods Orthotopic murine models of ovarian and uterine cancer were utilized to study the effect of MSC2363318A on survival and regression. For each cell line, 10 mice were treated in each of the experimental arms tested. Moreover, in vitro experiments in 21 cell lines (MTT, immunoblot analysis, plasmid transfection, reverse phase protein array [RPPA]) were carried out to characterize underlying mechanisms and potential biomarkers of response. All statistical tests were two-sided. Results MSC2363318A decreased tumor growth and metastases in multiple murine orthotopic models of ovarian (SKOV3ip1, HeyA8, and Igrov1) and uterine (Hec1a) cancer by reducing proliferation and angiogenesis and increasing cell death. Statistically significant prolonged overall survival was achieved with combination MSC2363318A and paclitaxel in the SKUT2 (endometrioid) uterine cancer mouse model ( P
- Published
- 2017
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