AKT inhibitors are a class of targeted therapy designed to interfere with the function of the protein kinase B (AKT) enzyme. AKT is a central component of a major signaling network within cells that often goes awry in cancer. The development of these small-molecule drugs focuses on blocking the enzyme’s activity to halt the uncontrolled proliferation and survival mechanisms of malignant cells. This therapeutic approach is significant because the targeted pathway is one of the most frequently hyperactivated in human tumors, offering a new avenue for treating resistant cancers.
Understanding the AKT Signaling Pathway
AKT is a serine/threonine-specific protein kinase that acts as a relay point in the PI3K/AKT/mTOR signaling cascade. This pathway regulates several basic cellular processes, including cell survival, growth, proliferation, and metabolism. Activation occurs when external signals, such as growth factors, bind to specific cell surface receptors, initiating a chain reaction inside the cell.
The process begins with the activation of Phosphoinositide 3-kinase (PI3K), which converts the lipid PIP2 into the messenger PIP3 in the cell membrane. PIP3 serves as a docking site, recruiting AKT to the membrane where it is phosphorylated and activated by kinases like PDK1. Active AKT then moves throughout the cell to phosphorylate numerous downstream target proteins, passing the “grow and survive” signal to effectors like mTOR, GSK3\(beta\), and FOXO.
The continuous transmission of this signal instructs the cell to increase protein synthesis, promote energy uptake, and inhibit programmed cell death, or apoptosis. This normal signaling is kept in check by the tumor suppressor protein PTEN. PTEN counteracts PI3K by converting PIP3 back to PIP2, essentially turning the signal off.
When AKT Drives Disease Progression
The AKT pathway drives cancer when its regulatory mechanisms are compromised, leading to constant and inappropriate activation. This hyperactivity is often rooted in specific genetic alterations, such as mutations in the \(PIK3CA\) gene, amplification of the \(AKT1\) gene, or the functional loss of the PTEN tumor suppressor. When PTEN is missing or mutated, the pathway’s brake is removed, resulting in PIP3 accumulation and a permanent “on” signal for AKT.
This uncontrolled activation translates directly into the aggressive characteristics of cancer cells by bypassing normal regulatory checkpoints. Active AKT promotes unchecked cell division by inhibiting cell cycle suppressors like p21 and p27, and stimulating pro-proliferative proteins like Cyclin D1. Furthermore, AKT prevents apoptosis by inactivating pro-apoptotic proteins such as BAD and activating proteins like MDM2, which tags the tumor suppressor p53 for degradation.
The pathway’s malfunction also contributes to other malignant processes, including resistance to chemotherapy and radiation. By sustaining cell survival despite DNA damage or cytotoxic drugs, hyperactive AKT signaling allows tumors to evade treatment and progress.
How AKT Inhibitors Work
AKT inhibitors interrupt the enzyme’s signaling process, blocking the uncontrolled growth and survival of cancer cells. These inhibitors operate through distinct mechanisms that target different parts of the AKT protein structure. The two primary classes are ATP-competitive and allosteric inhibitors, both designed to prevent the enzyme from carrying out its function of phosphorylation.
ATP-competitive inhibitors work by mimicking the cell’s main energy source, adenosine triphosphate (ATP), and fitting into the active site where ATP normally binds. By occupying this pocket, drugs like Capivasertib and Ipatasertib prevent the necessary transfer of a phosphate group from ATP to AKT’s substrate proteins. This competition effectively shuts down the downstream signaling cascade by starving the enzyme of the energy needed for phosphorylation.
Allosteric inhibitors employ a different strategy by binding to a location on the AKT protein separate from the active site, often the pleckstrin homology (PH) domain. Binding to this allosteric site changes the overall three-dimensional shape of the AKT protein. This conformational change prevents AKT from being recruited to the cell membrane, a necessary step for its activation by upstream kinases.
The Current Landscape of Clinical Trials
The development of AKT inhibitors has progressed significantly, with several compounds moving through late-stage clinical trials and one receiving regulatory approval. These trials focus on cancer types where the PI3K/AKT pathway is frequently altered, such as breast, prostate, and ovarian cancers. Pan-AKT inhibitors, which target all three AKT isoforms (AKT1, AKT2, and AKT3), have demonstrated the most promise.
Capivasertib is a prominent example, having received FDA approval for use in specific cases of hormone receptor-positive, HER2-negative advanced breast cancer. It is administered in combination with the endocrine therapy fulvestrant for patients whose tumors harbor \(PIK3CA\), \(AKT1\), or \(PTEN\) alterations and have progressed on prior treatment.
Another inhibitor, Ipatasertib, has been evaluated in clinical settings, including in triple-negative breast cancer (TNBC) and metastatic castration-resistant prostate cancer (mCRPC). In trials like LOTUS, adding Ipatasertib to standard chemotherapy like paclitaxel showed improvement in progression-free survival for TNBC patients. Current research favors combination therapy, using AKT inhibitors alongside standard treatments or other targeted drugs to overcome resistance.