Biochemistry & Pharmacology: Open Access
Open Access

Aberrant Protein Kinase Activity in Cancer: Mechanisms of Oncogenesis and Therapeutic Implications

Cristina Briscoe^{* *}Correspondence: Cristina Briscoe, Department of Pharmacology, University of Toronto, Toronto, Canada, Email:

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About the Study

Protein kinases are a large family of enzymes that play an important role in regulating various cellular processes, such as cell growth, division, differentiation, and apoptosis. These enzymes function by transferring a phosphate group from Adenosine Tri Phosphate (ATP) to specific amino acids on target proteins, a process known as phosphorylation. This phosphorylation serves as a molecular switch that can activate or deactivate proteins, thereby modulating their activity, stability, and interactions. Protein kinases are particularly significant due to their involvement in signaling pathways that control cell proliferation and survival. Aberrant regulation of protein kinases, through overexpression, mutations, or other mechanisms, can contribute to uncontrolled cell growth and cancer progression.

One of the major challenges in cancer treatment is drug resistance, where cancer cells become less responsive or completely unresponsive to therapeutic agents over time. Protein kinases play an important role in this phenomenon by influencing several mechanisms that cancer cells use to avoid drug-induced cell death. Drug resistance can be intrinsic, present before treatment, or acquired, developing during the course of treatment. The involvement of protein kinases in drug resistance is complex and adaptable, reflecting their central role in many of the pathways that determine cell survival and proliferation.

Protein kinases can contribute to drug resistance through various mechanisms. One common mechanism is through the activation of alternative signaling pathways. Cancer cells are highly adaptable, and when a key signaling pathway is blocked by a targeted therapy, they often find a way to ignore the inhibition by activating an alternative pathway that can promote survival and proliferation. For instance, when a particular kinase is targeted by a drug, mutations or alterations in other kinases may occur, leading to the activation of compensatory pathways that help the cancer cell survive. This ability to reconnect signaling networks and use alternative pathways highlights the complexity of targeting protein kinases in cancer therapy.

Another way in which protein kinases contribute to drug resistance is through mutations that alter the binding site of the drug. Many kinase inhibitors are designed to fit into the ATPbinding pocket of the kinase, thereby preventing ATP from binding and inhibiting the kinase's activity. However, mutations in the kinase domain can change the shape or charge of the binding pocket, reducing the drug’s ability to bind effectively. This structural alteration leads to reduced drug efficacy and the emergence of resistant cancer cells. These mutations can be particularly problematic because they often occur after treatment has begun, leading to acquired resistance.

Protein kinases are also involved in the regulation of drug efflux and drug metabolism, which are important factors in drug resistance. Efflux pumps are transport proteins that are located on the cell membrane and can actively pump drugs out of the cell, reducing the intracellular concentration of the therapeutic agent and diminishing its effectiveness. Protein kinases can regulate the expression and activity of these efflux pumps, such as the ATP-Binding Cassette (ABC) transporters, thereby enhancing the ability of cancer cells to resist drug treatment. Additionally, protein kinases can modulate the activity of enzymes involved in drug metabolism, altering the rate at which a drug is processed and inactivated within the cell.

One of the most important roles of protein kinases is in the regulation of apoptosis, or programmed cell death. Apoptosis is a mechanism by which cells can self-destruct in response to damage or stress, and it is a critical defense against cancer development. However, many cancer cells develop resistance to apoptosis, allowing them to survive and proliferate despite the presence of DNA damage or other signals that would normally trigger cell death. Protein kinases can contribute to this resistance by modulating the signaling pathways that control apoptosis. For example, certain kinases may activate survival pathways or inhibit pro-apoptotic proteins, thereby preventing the cell from undergoing apoptosis. One of the main characteristics of cancer is its resistance to apoptosis, which is closely related to medication resistance.