MK-2206, an AKT Inhibitor, Promotes Caspase-Independent Cell Death and Inhibits Leiomyoma Growth

Abstract

Uterine leiomyomas (ULs), benign tumors of the myometrium, are the number one indication for hysterectomies in the United States due to a lack of an effective alternative therapy. ULs show activation of the pro-survival AKT pathway compared with normal myometrium; however, substantial data directly linking AKT to UL cell survival are lacking. We hypothesized that AKT promotes UL cell survival and that it is a viable target for inhibiting UL growth. We used the investigational AKT inhibitor MK-2206, currently in phase II trials, on cultured primary human UL and myometrial cells, immortalized leiomyoma cells, and in leiomyoma grafts grown under the kidney capsule in mice. MK-2206 inhibited AKT and PRAS40 phosphorylation but did not regulate serum- and glucocorticoid-induced kinase and ERK1/2, demonstrating its specificity for AKT. MK-2206 reduced UL cell viability and decreased UL tumor volumes. UL cells exhibited disruption of mitochondrial structures and underwent cell death that was independent of caspases. Additionally, mammalian target of rapamycin and p70S6K phosphorylation were reduced, indicating that mammalian target of rapamycin complex 1 signaling was compromised by AKT inhibition in UL cells. MK-2206 also induced autophagy in UL cells. Pretreatment of primary UL cells with 3-methyladenine enhanced MK-2206-mediated UL cell death, whereas knockdown of ATG5 and/or ATG7 did not significantly influence UL cell viability in the presence of MK-2206. Our data provide molecular evidence for the involvement of AKT in UL cell survival and suggest that AKT inhibition by MK-2206 may be a viable option to consider for the treatment of ULs.

Progesterone Receptor Isoforms, Nuclear Corepressor-1 and Steroid Receptor Coactivator-1 and B-Cell Lymphoma 2 and Akt and Akt Phosphorylation Status in Uterine Myomas after Ulipristal Acetate Treatment: A Systematic Immunohistochemical Evaluation

“…The pathophysiology of myomas appears to involve Akt signaling, since myomas show higher levels of Akt than myometrium as well as aberrant Akt activation (identified by its phosphorylation, p-Akt) [7], which is essential for their growth and survival [64, 69]. Progesterone mediates rapid changes in myoma cells through a non-genomic PR signaling pathway [44] that phosphorylates Akt at Ser473 [13].…”

Activation of the MAPK/ERK Cell-Signaling Pathway in Uterine Smooth Muscle Cells of Women With Adenomyosis

“…It has been hypothesized that increased pAKT could be related to the overexpression of steroid receptors and receptor tyrosine kinases in leiomyomas. 47,48 Adenomyosis and endometriosis are both characterized by ectopic endometrial glands and stroma that have an invasive and hyperproliferative phenotype. Both entities often coexist and contribute to the same symptoms -infertility and pain symptoms -and the extent of both should be evaluated when deciding on a medical or surgical treatment strategy.…”

Signaling Pathways in Leiomyoma: Understanding Pathobiology and Implications for Therapy

“…For example, Sefton and colleagues (118) demonstrated that Akt inhibition by MK-2206, an investigational drug currently in phase II trials, inhibits leiomyoma growth and induces cellular death. In addition, there is a published patent to use an mTOR inhibitor as a treatment of leiomyoma (119).…”