Capivasertib Mechanism of Action: AKT Inhibition, Tumor Control

Capivasertib is an investigational cancer therapy designed to target a key signaling pathway involved in tumor growth and survival. Its development addresses the need for more precise treatments that disrupt cancer cell proliferation while minimizing effects on normal tissues.

By interfering with critical cellular processes, this drug has shown promise in preclinical and clinical studies. Understanding its mechanism of action provides insight into how it may contribute to improved cancer treatment strategies.

Classification As An AKT Inhibitor

Capivasertib belongs to a class of targeted cancer therapies known as AKT inhibitors, designed to interfere with the serine/threonine kinase AKT, a central regulator of cell survival and proliferation. AKT, also referred to as protein kinase B (PKB), is a key component of the phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling cascade, frequently dysregulated in cancer. Genetic alterations such as PI3K mutations, PTEN loss, or AKT amplification can lead to hyperactivation of this pathway, driving tumor progression and resistance to conventional therapies. By selectively targeting AKT, capivasertib aims to restore regulatory control over aberrant signaling, limiting tumor growth.

Capivasertib achieves specificity by binding to the ATP-binding pocket of all three AKT isoforms (AKT1, AKT2, and AKT3). This broad inhibition is particularly relevant in oncology, as different isoforms contribute to distinct aspects of tumor biology. AKT1 promotes cell survival, AKT2 influences metastasis and glucose metabolism, and AKT3 has been linked to tumor progression in cancers such as melanoma and glioblastoma. By targeting all three, capivasertib provides a comprehensive approach to suppressing AKT-driven oncogenic processes, distinguishing it from earlier inhibitors with isoform selectivity and limited efficacy.

Clinical trials have demonstrated capivasertib’s therapeutic potential in cancers with PI3K/AKT pathway alterations. The CAPItello-291 trial, a phase III study evaluating capivasertib with fulvestrant for hormone receptor-positive, HER2-negative breast cancer, showed that patients with AKT pathway mutations had significantly improved progression-free survival compared to those receiving fulvestrant alone. These findings highlight the relevance of AKT inhibition in tumors with pathway dysregulation and capivasertib’s role in overcoming resistance to endocrine therapy.

Molecular Interaction With AKT

Capivasertib inhibits AKT by binding to its kinase domain within the ATP-binding pocket, preventing ATP from accessing the catalytic site. This interaction disrupts phosphorylation events required for AKT activation, halting its downstream functions. Structural studies show that capivasertib stabilizes the inactive state of AKT, reducing enzymatic activity across all three isoforms.

Capivasertib also interferes with AKT’s localization within the cell. Under normal conditions, AKT is recruited to the plasma membrane via interactions with phosphatidylinositol-3,4,5-trisphosphate (PIP3), allowing phosphorylation at threonine 308 (T308) and serine 473 (S473). By locking AKT in an inactive conformation, capivasertib prevents this phosphorylation cascade, impairing its ability to propagate oncogenic signals. Studies using phospho-AKT immunoblotting confirm that capivasertib reduces AKT phosphorylation in a dose-dependent manner, reinforcing its role as a potent kinase inhibitor.

Beyond direct inhibition, capivasertib promotes AKT degradation through proteasomal pathways. Prolonged inhibition triggers feedback mechanisms that enhance ubiquitin-mediated proteolysis, leading to a sustained decrease in AKT protein levels. Preclinical models demonstrate that capivasertib not only suppresses AKT phosphorylation but also lowers total AKT expression over time, amplifying its inhibitory effect.

Effects On Downstream Signaling

Blocking AKT activity with capivasertib disrupts multiple downstream signaling cascades that regulate tumor cell behavior. One immediate consequence is the inhibition of glycogen synthase kinase 3 (GSK3), a substrate of AKT involved in cell cycle control and metabolism. Normally, AKT phosphorylates and inhibits GSK3, allowing cancer cells to bypass growth restrictions. Capivasertib reverses this suppression, reactivating GSK3, which destabilizes oncogenic proteins such as MYC and cyclin D1. The reduction in these proliferative drivers contributes to impaired tumor cell cycle progression and diminished metabolic adaptability.

Capivasertib also suppresses mTOR complex 1 (mTORC1) signaling. Under normal conditions, AKT phosphorylates tuberous sclerosis complex 2 (TSC2), preventing it from inhibiting mTOR activity. Capivasertib restores TSC2 function, reducing mTORC1 signaling. This decline leads to decreased protein synthesis and impaired ribosomal biogenesis, both crucial for tumor growth. The effects are particularly evident in cancers highly dependent on the PI3K/AKT/mTOR axis, such as hormone receptor-positive breast cancer and certain prostate cancers.

Another key effect is the activation of FOXO transcription factors. AKT normally phosphorylates FOXO proteins, sequestering them in the cytoplasm and preventing them from activating genes involved in cell cycle arrest and oxidative stress resistance. With capivasertib blocking this phosphorylation, FOXO proteins translocate into the nucleus, upregulating genes such as p27 and BIM, which promote cell cycle inhibition and apoptosis. This shift in gene expression creates a more hostile environment for tumor survival.

Changes In Tumor Cell Proliferation

Capivasertib significantly alters tumor cell proliferation by disrupting key checkpoints regulating cell cycle progression. One major effect is the reduction in cyclin D1 levels, a key regulator of the G1-to-S phase transition. AKT stabilizes cyclin D1 by preventing its degradation through the ubiquitin-proteasome system. When capivasertib inhibits AKT, cyclin D1 undergoes accelerated degradation, leading to prolonged G1 phase and reduced DNA synthesis. This disruption is particularly relevant in cancers with dysregulated cyclin D1 expression, such as estrogen receptor-positive breast cancer and certain lymphomas.

Capivasertib also impairs mitotic progression by affecting polo-like kinase 1 (PLK1), a mitotic kinase ensuring proper chromosomal segregation and spindle formation. AKT-mediated phosphorylation enhances PLK1 stability, promoting rapid cell division. With capivasertib blocking this input, PLK1 activity declines, increasing the likelihood of mitotic errors and subsequent cell cycle arrest. This disruption is particularly detrimental to highly proliferative tumors, where even minor delays in cell division can compromise survival.

Influence On Apoptotic Regulation

Capivasertib not only suppresses tumor cell proliferation but also enhances apoptotic signaling. AKT is a well-established inhibitor of apoptosis, primarily through its regulation of pro- and anti-apoptotic proteins. By disrupting AKT activity, capivasertib shifts the balance in favor of apoptosis, increasing cancer cell susceptibility to cell death. This effect is particularly relevant in tumors that resist apoptotic triggers due to hyperactive AKT signaling, such as those with PTEN loss or PI3K mutations. Restoring apoptotic sensitivity enhances the effectiveness of combination therapies, particularly with cytotoxic agents or targeted inhibitors.

Capivasertib enhances apoptosis by regulating BCL-2 family proteins. AKT-mediated phosphorylation stabilizes anti-apoptotic proteins such as BCL-2 and MCL-1 while inhibiting pro-apoptotic factors like BAD and BIM. With AKT inhibition, this protective phosphorylation is lost, leading to increased degradation of survival-promoting proteins and activation of apoptotic effectors. Studies show that capivasertib treatment increases cleaved caspase-3 and PARP, both hallmarks of apoptotic execution. This shift in apoptotic regulation is particularly beneficial in cancers that evade cell death through AKT-driven survival pathways, including triple-negative breast cancer and certain hematologic malignancies.