By seamlessly bridging real-world pharmacovigilance with advanced structural biology and single-cell transcriptomics, this study delineates the comprehensive safety landscape of capivasertib. Our findings provide crucial clinical alerts for AE monitoring and offer deep mechanistic insights to optimize personalized therapeutic management in breast cancer.

The immunosuppressive effect mediated by MAPK12 overexpression was blocked by the PI3K inhibitor LY294002. MAPK12 knockdown restricted tumor growth and extended survival in mice, accompanied by increased CD8+ T cell infiltration. In summary, MAPK12 promotes HCC immune escape by upregulating PD-L1 via the PI3K/Akt/mTOR pathway.

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.

We highlight the recent results from the Phase III CAPItello-281 trial (NCT04493853) demonstrating that the addition of capivasertib to abiraterone acetate and androgen deprivation therapy (ADT) significantly improved radiographic progression-free survival in patients with PTEN-deficient mCSPC, leading to the FDA-approval of this regimen. Notable adverse events in the cabavisertib arm included hyperglycemia, diarrhea, and rash. CAPItello-281 addresses a significant unmet need for PTEN-deficient mCSPC, suggesting AKT inhibition as a potential new targeted treatment strategy for a sub-population with poor prognosis.

P2, N=108, Completed, National Cancer Institute (NCI) | Active, not recruiting --> Completed | Trial completion date: Mar 2027 --> May 2026

P2, N=29, Recruiting, Sabine Mueller, MD, PhD | Not yet recruiting --> Recruiting

P2, N=110, Recruiting, Dana-Farber Cancer Institute | N=180 --> 110

By applying the pathway inhibitor LY294002, it was confirmed that the PI3K/Akt pathway is crucial for osteosarcoma proliferation. This study confirms that PYCR1 drives osteosarcoma cell proliferation and migration through three key mechanisms: regulating downstream genes, inhibiting ferroptosis, and activating the PI3K/Akt signaling pathway.

In vivo, capivasertib significantly suppressed tumor growth and its combination with cisplatin significantly prolonged survival in xenograft models without inducing overt systemic toxicity. Mechanistically, capivasertib treatment increased AKT phosphorylation, consistent with pharmacodynamic target engagement, while suppressing downstream mTOR/4EBP1 signaling and inducing pro-apoptotic levels. Collectively, these findings demonstrate that Akt/mTOR inhibition by capivasertib enhances therapeutic efficacy in preclinical NPC models and provides rationale for further clinical evaluation of capivasertib in advanced NPC.

Importantly, combining the PI3K/AKT inhibitor PKI-587 with the PARP inhibitor BMN673 synergistically inhibits tumor growth across multiple SCLC models, including cell lines, patient-derived organoids, and xenograft models. Collectively, our findings define a "PI3K/AKT-STAT5A-TRIM21-PARP1" axis critical for SCLC progression and propose its dual inhibition as a promising therapeutic strategy.

Functional relevance of AKT signaling was evaluated using siRNA knockdown, MK2206, and SC79...EEDJF exerts anti-colorectal cancer effects in vitro, potentially associated with regulation of PI3K-Akt/p21 signaling. These findings provide a basis for further studies on the bioactive constituents, pharmacological mechanisms, and in vivo efficacy of DJF-derived preparations.

GOLPH3, which is overexpressed in PRAD, may enhance glucose metabolic activity in PRAD cells in association with activation of the PI3K/AKT/mTOR pathway, thereby supporting PRAD cell proliferation. These findings provide basic mechanistic evidence for the role of GOLPH3 in PRAD cell metabolism, but further clinical studies are required to determine its prognostic or therapeutic relevance.