Cancer degronopathies and protein-fate biomarkers in drug resistance and cancer progression: signalling mechanisms, measurement and translational limits

Abstract

Drug resistance remains a major barrier to durable targeted therapy, and cancer progression often reflects rewiring of signalling pathways that control protein stability. Dysregulation of the ubiquitin–proteasome system, including failure of degron-dependent substrate recognition, can stabilise oncogenic proteins, accelerate tumour-suppressor loss and generate treatment-dependent protein states. Yet clinical interpretation commonly relies on genotype or steady-state abundance, neither of which directly identifies the degradation rate or route of a specific substrate. In this critical narrative review, we use cancer degronopathy as a restricted operational term for tumour-relevant alterations in degron-dependent recognition, rather than as an established disease or diagnostic class. Through contrastive analysis of four endogenous modules (SPOP; FBXW7 versus CTNNB1; KEAP1–NFE2L2–CUL3; and VHL–HIF), together with drug-induced degradation, we examine how altered protein fate intersects with signalling pathways implicated in cancer progression, intrinsic or acquired drug resistance and therapeutic response. We trace each candidate biomarker from the initiating tumour event and substrate-specific fate change to patient-compatible measurement, analytical performance and intended clinical use. The analysis shows that SPOP effects vary with allele, substrate, lineage and assembly; FBXW7 reader defects and CTNNB1 cis-acting escape require different analytes; and pooled KEAP1-axis states and cross-isoform VHL–HIF extrapolations remain unresolved. Pharmacological degradation adds a temporal layer: vepdegestrant acts through oestrogen receptor-α degradation, whereas its FDA-authorised companion diagnostic selects patients by plasma ESR1 genotype, and serial target measurements are required to distinguish productive target loss, failed loss, recovery and downstream escape. Protein-fate measurement may be informative if it resolves a reproducible, decision-relevant state that genotype, abundance or pathway-output markers leave ambiguous. We define the experimental and clinical evidence needed to test whether such measurements can inform precision strategies to address drug resistance and cancer progression. Conclusion remain limited to the contrastive cases and United States records reviewed through 26 July 2026, with separately dated updates to selected trial records.