Combined treatment of uterine leiomyosarcoma with gamma secretase inhibitor MK-0752 and chemotherapeutic agents de-creases cellular invasion and increases apoptosis

Uterine leiomyosarcoma (uLMS) is a rare and aggressive malignancy with treat-ments that have limited efficacy and often have significant toxicities. We previously demonstrated the presence of Notch signaling in uLMS as well as decreased cell viability and Notch expression after inhibition using the gamma secretase inhibitor, MK-0752. The aim of this study was to assess the combination of MK-0752 and chemotherapeutics commonly used for the treatment of uLMS. Using two human uLMS cell lines, SK-UT-1B and SK-LMS-1, we investigate the role of MK-0752 alone and in combination with docetaxel and gemcitabine. We demonstrated synergism between MK-0752 and docetaxel and gemcitabine using MTT assays. These synergistic combinations were used in transwell invasion assays, cell cycle flow cytometry, and proliferation assays. We found decreased invasion and an increase in the apoptotic sub-G1 cell cycle population after combination treatment. The combinations of MK-0752 with gemcitabine and docetaxel is a potential novel therapeutic approach for uLMS. Overall design: SK-LMS-1 and SK-UT-1B cells were exposed to the IC30 of MK-0752 alone, MK-0752 in combination with gemcitabine and docetaxel, or DMSO volue control for 72 hours, at which time cells were harvested and RNA extraction was performed Comparative gene and pathway analysis was performed on data obtained from RNA seq of both cells lines and treatment combinations