Inhibition of PI3K-Dependent Endometrial Cancer: The Efficacy of ARQ 092 and ARQ 751 Allosteric AKT Inhibitors

Endometrial cancer is often characterized by the overactivation of the AKT pathway, which is linked to more aggressive disease and poorer outcomes. Two AKT inhibitors, ARQ 092 and ARQ 751, are being investigated for their potential in treating this cancer. ARQ 092 is currently in clinical trials, while ARQ 751 represents a next-generation inhibitor with distinct properties.

Both compounds were assessed for their impact on AKT signaling and cell viability in an endometrial cancer cell line with an activated PI3K mutation. They showed dose-dependent inhibition of AKT signaling and significant anti-proliferative effects, with ARQ 751 being more potent than ARQ 092.

When tested in patient-derived tumor models (PDX), a response rate of over 50% was observed in 12 out of 22 models. In an in vivo mouse xenograft model, both inhibitors led to substantial AKT inhibition and significant tumor growth reduction, with ARQ 751 showing a slightly higher efficacy rate.

Pharmacokinetic studies in mice indicated that the plasma concentration of ARQ 092 at a 100 mg/kg dose was comparable to that observed in human patients at the doses tested in the Phase I clinical trial. Notably, one patient with a PIK3CA mutation enrolled in the expanded cohort of the ARQ 092-101 trial exhibited a durable partial response to the treatment.

In conclusion, ARQ 092 and ARQ 751 have both shown the ability to potently inhibit AKT signaling and exhibit antitumor activity in endometrial cancer cells. The early clinical response observed in a patient with a PIK3CA mutation supports the continued evaluation of these inhibitors in the treatment of endometrial cancers driven by the PI3K pathway.