Protein Expression to Functional Interaction: Evaluating Evidence for Therapeutic Targets in Cancer

Abstract

Protein abundance helps identify candidate cancer targets. Their therapeutic relevance depends on the protein’s molecular state, its role in the tumor, and how the treatment acts on it. This review synthesizes evidence from quantitative proteomics, protein interaction mapping, structural analysis, genetic perturbation, and pharmacological studies. Preclinical examples involving epidermal growth factor receptor trafficking, hexokinase 2 scaffolding, chromatin complex assembly, and protein turnover illustrate how localization, binding partners, and post-translational modifications shape protein function. Studies of targeted degraders and molecular glues show why target engagement, ubiquitin ligase recruitment, and protein loss require separate verification. Clinical responses to revumenib in genetically defined acute leukemias support targeting the menin–KMT2A interaction, while acquired MEN1 mutations reveal a mechanism of resistance. Trastuzumab deruxtecan in HER2-low breast cancer illustrates a distinct use of protein expression to guide patient selection when the target serves as a delivery antigen. We propose a framework that evaluates protein expression, physical interaction, functional dependence, drug mechanism, and clinical benefit as distinct forms of evidence. The framework matches validation experiments and patient-selection biomarkers to the therapeutic modality. Confidence in a target is greatest when independent evidence connects the proposed mechanism to a cancer-relevant effect at achievable and tolerable drug exposures.

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