Not the comfy chair! Cancer drugs that act against multiple active sites

Area of Science:

• Oncology
• Pharmacology
• Molecular Biology

Background:

• Small molecule kinase inhibitors were developed based on catalytic site inhibition.
• Kinase inhibitors targeting ATP binding sites have predicted on-target specificity but also unknown off-targets due to conserved ATP pockets.
• The "on-target off-target biology" of kinase inhibitors means their therapeutic effects can stem from unknown biological processes.

Purpose of the Study:

• To discuss drug therapies whose actions are not explained by their primary kinase target.
• To propose a methodology for screening cell signaling changes.
• To address the limitations of personalized medicine in treating heterogeneous malignancies.

Main Methods:

• Review of drug therapies and their mechanisms of action.
• Discussion of in-cell western immunoblotting for screening cell signaling.
• Analysis of tumor heterogeneity and clonal evolution.

Main Results:

• Kinase inhibitors can exert anti-tumor effects through mechanisms beyond their initially targeted kinase.
• In-cell western immunoblotting offers a method to investigate these signaling alterations.
• Tumor clonal evolution in treated patients leads to heterogeneity, complicating single-target therapies.

Conclusions:

• Therapeutic benefits of kinase inhibitors may arise from inhibiting unintended targets.
• A shift in therapeutic strategy is needed beyond targeting single mutated oncogenes.
• The complexity of cancer necessitates approaches that account for tumor heterogeneity and off-target effects.