AKT Biological Pathways Reviews
AKT (protein kinase B) is a serine threonine kinase that plays a pivotal role in regulating many cell processes, including survival, proliferation, invasion, apoptosis, and angiogenesis.1 Disruptions in the AKT pathway are associated with cancer, diabetes, cardiovascular and neurological diseases.2 In breast cancer, AKT is disrupted in up to 70% of cases, making it a valuable therapeutic target.3 Receptor tyrosine kinases can be used to activate the AKT pathway, signaling downstream effects like cell metabolism, proliferation, and survival.1
Many patients with hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer experience treatment resistance and disease progression after first-line treatment with a CDK4/6 inhibitor and endocrine therapy.4 The role of the AKT pathway in treatment resistance is not entirely known, though research suggests it may be more involved than previously recognized.1,5
Hyperactivation of the AKT pathway after CDK4/6 inhibition and endocrine therapy can drive disease progression.4 Aberrations associated with potential increase in AKT pathway activity include loss of PTEN function, hyperactivating mutations, and crosstalk with other signaling pathways.6,7 AKT hyperactivation causes increased cell proliferation, dysregulated cell cycle progression, increased ER expression, and amplified downstream ER signaling.1,5,8
AKT in Breast Cancer
In breast cancer, the majority of patients have disruptions along the AKT pathways, with disruption reported in up to 70% of cases.
AKT Pathway Inhibitors
The AKT pathway is a cellular signaling pathway that controls cell growth and is overactivated in many cancers. Inhibiting AKT activity using AKT inhibitors is associated with a reduction in tumor cell proliferation. This table outlines therapies targeting the AKT pathway both approved by the FDA and in the pipeline.
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AKT Pathway Inhibitors Approved by the FDA |
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Brand Name (Generic Drug Name) |
Indications |
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Truqap (Capivasertib) |
Capivasertib is approved in combination with fulvestrant for adult patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breast cancer with one or more PIK3CA/AKT1/PTEN-alterations, as detected by an FDA-approved test, following progression on at least one endocrine-based regimen in the metastatic setting or recurrence on or within 12 months of completing adjuvant therapy.1 |
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AKT Pathway Inhibitors in the Pipeline |
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Ipatasertib (RG7440)2 |
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Afuresertib (GSK2110183)3 |
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Uprosertib (GSK2141795)3 |
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Drug Table References:
- US Food and Drug Administration. FDA approves capivasertib with fulvestrant for breast cancer. Published November 16, 2023. Accessed December 12, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-capivasertib-fulvestrant-breast-cancer
- Genentech. Ipatasertib (AKT Inhibitor). Accessed December 12, 2023. https://www.genentechoncology.com/pipeline-molecules/ipatasertib.html
- Uko NE, Güner OF, Matesic DF, Bowen JP. Akt Pathway Inhibitors. Curr Top Med Chem. 2020;20(10):883-900. doi: 10.2174/156802662066200224101808.
