PI3K/AKT/mTOR inhibition in combination with doxorubicin is an effective therapy for leiomyosarcoma

Abstract

BackgroundLeiomyosarcoma (LMS) is a common type of soft tissue sarcoma that responds poorly to standard chemotherapy. Thus the goal of this study was to identify novel selective therapies that may be effective in leiomyosarcoma by screening cell lines with a small molecule library comprised of 480 kinase inhibitors to functionally determine which signalling pathways may be critical for LMS growth.MethodsLMS cell lines were screened with the OICR kinase library and a cell viability assay was used to identify potentially effective compounds. The top 10 % of hits underwent secondary validation to determine their EC50 and immunoblots were performed to confirm selective drug action. The efficacy of combination drug therapy with doxorubicin (Dox) in vitro was analyzed using the Calcusyn program after treatment with one of three dosing schedules: concurrent treatment, initial treatment with a selective compound followed by Dox, or initial treatment with Dox followed by the selective compound. Single and combination drug therapy were then validated in vivo using LMS xenografts.ResultsCompounds that targeted PI3K/AKT/mTOR pathways (52 %) were most effective. EC50s were determined to validate these initial hits, and of the 11 confirmed hits, 10 targeted PI3K and/or mTOR pathways with EC50 values <1 μM. We therefore examined if BEZ235 and BKM120, two selective compounds in these pathways, would inhibit leiomyosarcoma growth in vitro. Immunoblots confirmed on-target effects of these compounds in the PI3K and/or mTOR pathways. We next investigated if there was synergy with these agents and first line chemotherapy doxorubicin (Dox), which would allow for earlier introduction into patient care. Only combined treatment of BEZ235 and Dox was synergistic in vitro. To validate these findings in pre-clinical models, leiomyosarcoma xenografts were treated with single agent and combination therapy. BEZ235 treated xenografts (n = 8) demonstrated a decrease in tumor volume of 42 % whereas combining BEZ235 with Dox (n = 8) decreased tumor volume 68 % compared to vehicle alone.ConclusionsIn summary, this study supports further investigation into the use of PI3K and mTOR inhibitors alone and in combination with standard treatment in leiomyosarcoma patients.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-016-0814-z) contains supplementary material, which is available to authorized users.

Enhanced Anticancer Activity of PF-04691502, a Dual PI3K/mTOR Inhibitor, in Combination With VEGF siRNA Against Non–small-cell Lung Cancer

“…28 Kinetic studies of PF0 and other PI3K/mTOR dual inhibitors had shown that levels of p-Akt (S473) and p-p70S6K (T389) decrease below control levels after 3 to 72 hours treatment. 47,48,49 This is in agreement with our results showing that phosphorylation of Akt and p70S6K was significantly ( P < 0.05) inhibited after 24–72 hours.…”

Dihydromyricetin protects neurons in an MPTP-induced model of Parkinson's disease by suppressing glycogen synthase kinase-3 beta activity

“…DHM inhibition of GSK-3β activity may contribute to DA neuronal protection The phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt/ PKB) signaling pathway plays a key role in cell survival, proliferation and differentiation [29][30][31] . Akt is a direct downstream effector of the PI3K pathway and is activated by phosphorylation at Ser473.…”

Potential Targets' Analysis Reveals Dual PI3K/mTOR Pathway Inhibition as a Promising Therapeutic Strategy for Uterine Leiomyosarcomas—an ENITEC Group Initiative

“…New-generation inhibitors targeting also mTORC2, as well as PI3K, have not been tested in gynecologic sarcomas until very recently. SK-LMS-1, a vulvar leiomyosarcoma cell line, has proven to be sensitive to BEZ235, the same dual PI3K/mTOR inhibitor that we tested in our study (44). BEZ235 has also been shown to inhibit the proliferation of pazopanibresistant retroperitoneal undifferentiated pleomorphic sarcoma (UPS) cells (45).…”