What is AKT?
AKT, also known as Protein Kinase B (PKB), is a serine/threonine-specific protein kinase that plays a pivotal role in multiple cellular processes. These include glucose metabolism, apoptosis, cell proliferation, transcription, and cell migration. AKT is a central node in the
PI3K/AKT/mTOR signaling pathway, which is frequently implicated in cancer development and progression.
How is AKT Activated?
AKT activation is a multi-step process that starts with the binding of a
growth factor to a receptor tyrosine kinase (RTK) on the cell membrane. This leads to the activation of
phosphoinositide 3-kinase (PI3K), which in turn phosphorylates PIP2 to produce PIP3. PIP3 serves as a docking site for AKT and its activator PDK1. Upon docking, PDK1 phosphorylates AKT at threonine 308, partially activating it. Full activation requires additional phosphorylation at serine 473 by mTORC2.
Why is AKT Important in Cancer?
AKT is often referred to as the "survival kinase" because it promotes cell survival and growth. In cancer,
mutations or amplifications in genes encoding components of the PI3K/AKT/mTOR pathway lead to its constitutive activation. This results in unchecked cell proliferation, inhibition of apoptosis, and increased
metastasis. For instance, mutations in the
PTEN gene, a negative regulator of the pathway, are common in various cancers and lead to increased AKT activity.
How is AKT Related to Chemotherapy Resistance?
One of the significant challenges in cancer treatment is
chemotherapy resistance, and AKT plays a substantial role in this phenomenon. AKT can activate multiple downstream targets that promote DNA repair, inhibit apoptosis, and enhance drug efflux. This makes cancer cells more resilient to the cytotoxic effects of chemotherapy. For example, AKT activation can lead to the phosphorylation and inactivation of
pro-apoptotic proteins like BAD and caspase-9, thus helping cancer cells survive even in the presence of chemotherapeutic agents.
Are There Therapeutic Strategies Targeting AKT?
Given its central role in cancer, AKT is a promising target for cancer therapies. Several
AKT inhibitors are currently in clinical trials. These inhibitors can be classified into ATP-competitive inhibitors, allosteric inhibitors, and lipid-based inhibitors. Each class has distinct mechanisms of action and varying degrees of efficacy and toxicity. For instance, MK-2206 is an allosteric inhibitor that has shown promise in early-phase clinical trials.
What Are the Challenges in Targeting AKT?
Despite the potential, targeting AKT presents several challenges. One significant issue is the
redundancy and complexity of the PI3K/AKT/mTOR pathway. Inhibiting AKT alone may not be sufficient to halt cancer progression because cancer cells can activate alternative survival pathways. Additionally, systemic inhibition of AKT can lead to substantial
toxicity due to its role in normal cellular functions.
Future Directions
Future research aims to develop more specific and less toxic AKT inhibitors, as well as combination therapies that target multiple pathways concurrently. Personalized medicine approaches, which involve tailoring therapies based on an individual's specific genetic makeup, are also being explored. This could enhance the efficacy of AKT inhibitors and minimize resistance.
