Ipatasertib, an oral AKT inhibitor, in combination with carboplatin exhibits anti-proliferative effects in uterine serous carcinoma

Abstract

Purpose Uterine serous carcinoma (USC) exhibits worse survival rates compared to the endometrioid subtype, and there is currently no effective treatment options for recurrence of this disease after platinum-based chemotherapy. Activation of PIK3CA/AKT/mTOR signaling pathway is a common biological feature in USC. Materials and Methods Ipatasertib (IPAT) is an investigational, orally administered, ATP-competitive, highly selective inhibitor of pan AKT that has demonstrated anti-proliferative activity in a variety of tumor cells and tumor models. In this study, we used IPAT, carboplatin and their combination to investigate the anti-tumor activity in SPEC-2 and ARK-1 cells. Results Our results indicate that IPAT combined with carboplatin at low doses was more effective at reducing proliferation, inducing apoptosis and causing cellular stress than IPAT or carboplatin alone. In particular, inhibition of the PIK3CA/AKT/mTOR pathway and induction of DNA damage were involved in the synergistic inhibition by combination treatment of cell viability in USC cells treated with the combination. Furthermore, IPAT in combination with carboplatin significantly reduced cell adhesion and inhibited cell invasion. Conclusions These findings suggest that the combination of IPAT and carboplatin has potential clinical implications for developing new USC treatment strategies.

Molecular Targeting of the Phosphoinositide-3-Protein Kinase (PI3K) Pathway across Various Cancers

“…Ipatasertib (GDC0068) is an ATP-competitive pan-AKT inhibitor, which has been shown to have some efficacy in combination with carboplatin in uterine serous carcinoma, in combination with erdafitinib in bladder cancer cells, as well as to increase the sensitivity of endometrial cancer cells to paclitaxel in preclinical studies [205][206][207]. It also demonstrated clinical efficacy in combination with abiraterone in patients with metastatic prostate cancer with or without PTEN loss, in combination with paclitaxel in locally advanced or metastatic triple-negative breast cancer in LOTUS trial, and in combination with abiraterone in mCRPC with PTEN loss in IPATential150 [208][209][210].…”

Proteomic Assessment of SKBR3/HER2+ Breast Cancer Cellular Response to Lapatinib and Investigational Ipatasertib Kinase Inhibitors

“…Lapatinib is a reversible dual Tyr kinase inhibitor that targets both the HER2 and EGFR receptors by acting as an ATP-competitive small molecule that binds the intracellular catalytic region of the two kinases [4], while Ipatasertib, also a small molecule drug, inhibits the activity of all three Ser/Thr AKT kinase isomers [5,6]. Each of these drugs has shown promise in treating breast or other cancers alone or in combination with other therapeutic components [7][8][9][10][11]. In ~50 % of HER2+ breast cancers the PI3K/AKT pathway is altered as well, its hyperactivation leading to alternative pathways that lead to the development of drug resistance [7].…”