ipatasertib (RG7440)

Our study demonstrates recurrent activation of AKT kinases by copy number gains and upregulated expression in PM. Pharmacological AKT and mTOR inhibition is a promising therapeutic alternative for mesothelioma.

The results indicate that, in addition to off-target interactions with members of the AGC kinase family predicted for most ATP-competitive inhibitors, Ipatasertib and NTQ1062 may exhibit strong interactions with PI3Kα, a member of the PI3K kinase family, while NTQ1062 may also interact with mTOR, a member of the PI3K-related kinase family. However, further in vitro and in vivo studies are required to validate these potential interactions. Overall, this work establishes a hybrid deep learning and physics-based computational framework for predicting the off-target effects of ATP-competitive AKT1 inhibitors and provides mechanistic insights into kinase cross-reactivity within the PI3K/AKT/mTOR signaling pathway.

P1/2, N=1132, Recruiting, Hoffmann-La Roche | N=792 --> 1132

P2, N=54, Completed, Hospices Civils de Lyon | Unknown status --> Completed | Trial completion date: Oct 2023 --> Jun 2026 | Trial primary completion date: Oct 2023 --> Jun 2026

In addition, mTOR pathway activity and responsiveness to mTOR inhibitors (rapamycin and ipatasertib) and chemotherapeutic agents (cisplatin) were assessed. Compared with 2D monolayer cultures, 3D TMSs exhibited reduced mTOR signaling activity, which led to significantly decreased sensitivity to mTOR inhibition. These findings indicate that 3D bioprinted breast cancer models recapitulate key structural and signaling features of in situ tumors more accurately than 2D systems, highlighting their potential value for preclinical drug testing and mechanistic studies.

Emerging evidence supports synergistic potential of new-generation PLK1 inhibitors, such as Onvansertib, with chemo- and immune-therapies. This mini-review and perspective present current insights on PLK1 overexpression and its mechanistic impact on cancer aggressiveness and therapy resistance. We highlight the need for refined patient stratification and innovative combination regimens to exploit PLK1 inhibition in cancer treatment.

P1/2, N=314, Terminated, Hoffmann-La Roche | Completed --> Terminated; Study was closed early as the sponsor decided not to continue development of certain treatment combinations.

P2, N=146, Active, not recruiting, Queen Mary University of London | Trial completion date: Jan 2026 --> Aug 2026 | Trial primary completion date: Jan 2021 --> Aug 2026

The combination of fulvestrant, ipatasertib, and palbociclib showed preliminary signs of clinical activity and showed expected adverse events in heavily pretreated patients with HR+/HER2- metastatic breast cancer, warranting further evaluation in those with CDK4/6 inhibitor-refractory disease.

P1/2, N=792, Recruiting, Hoffmann-La Roche | N=56 --> 792

This is the first report in clinical samples showing that ipatasertib efficiently depletes FOXP3+ regulatory T cells and results in increased infiltration of effector CD8+ T cells in the tumor microenvironment. This was associated with preliminary efficacy in a subset of patients with treatment-refractory glioblastoma (GBM).

P1, N=46, Recruiting, National Cancer Institute (NCI) | Trial completion date: Jun 2026 --> Jul 2027 | Trial primary completion date: Jun 2026 --> Jul 2027