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AKT Inhibitors: New Weapons in the Fight Against Breast Cancer?

ABSTRACT: The serine/threonine kinase AKT is a key component of the PI3K/AKT/mTOR signaling pathway as it exerts a pivotal role in cell growth, proliferation, survival, and metabolism. Deregulation of this pathway is a common event in breast cancer including hormone receptor-positive (HR+) disease, HER2-amplified, and triple negative tumors. Hence, targeting AKT represents an attractive treatment option for many breast cancer subtypes, especially those resistant to conventional treatments. Several AKT inhibitors have been recently developed and two ATP-competitive compounds, capivasertib and ipatasertib, have been extensively tested in phase I and II clinical trials either alone, with chemotherapy, or with hormonal agents. Additionally, phase III trials of capivasertib and ipatasertib are already under way in HR+ and triple-negative breast cancer. While the identification of predictive biomarkers of response and resistance to AKT inhibition represents an unmet need, new combination strategies are under investigation aiming to boost the therapeutic efficacy of these drugs. As such, trials combining capivasertib and ipatasertib with CDK4/6 inhibitors, immune checkpoint inhibitors, and PARP inhibitors are currently ongoing. This review summarizes the available evidence on AKT inhibition in breast cancer, reporting both efficacy and toxicity data from clinical trials along with the available translational correlates and then focusing on the potential use of these drugs in new combination strategies.

SUBMITTER: Martorana F

PROVIDER: S-EPMC8118639 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The root of Panax notoginseng (P. notoginseng) is one of the most highly valuable medicinal herbs in China owing to its pronounced hemostatic and restorative properties. Despite this important fact, growing P. notoginseng is seriously limited by root-rot diseases. In studies aimed at developing a solution to this problem, environment-friendly essential oils (EOs) of five medicinal plants of the family Zingiberaceae were tested for their inhibitory effects on the growth of three main soil pathogens associated with the root-rot diseases of P. notoginseng. The results showed that the EOs of Alpinia katsumadai Hayata and Zingiber officinale Roscoe promote significant reductions in the mycelium growth of the pathogen in vitro at a concentration of 50 mg mL-1, which is much higher than that needed (5 mg mL-1) to reduce growth by the positive control, flutriafol. Furthermore, the chemical components of the two EOs were determined by using GC-MS analysis. Eucalyptol was found to account for more than 30% of the oils of the two plants, with the second major components being geranyl acetate and ?-terpineol. These substances display different degrees of fungistasis in vitro. To further determine the effects of the EO of Zingiber officinale (Z. officinale) in vivo, soilless cultivation of P. notoginseng with pathogen inoculation was conducted in a greenhouse. Addition of the petroleum ether extract (approximately equal to EO) of Z. officinale to the culture matrix causes a large decrease in both the occurrence and severity of the P. notoginseng root-rot disease. The decreasing trend of net photosynthetic rate (Pn), stomatal conductance (gs), intercellular CO2 concentration (Ci), and transpiration rate (Tr) were all alleviated. In addition, the activities of catalase (CAT), peroxidase (POD), and the malondialdehyde (MDA) content were also largely reduced after pathogen infection, with the root activity being higher than that of the control. Taken together, the findings reveal that the EOs from plants might serve as promising sources of eco-friendly natural pesticides with less chemical resistance.

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AKT Inhibitors: New Weapons in the Fight Against Breast Cancer?

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