# Destroy the truncated androgen receptor that hormone drugs cannot touch

Source: https://onco.cc/ideas/idea-bio1-arv7-degrader/  
OnCo record `idea-bio1-arv7-degrader` (Idea). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

In advanced prostate cancer the AR-V7 splice variant of the androgen receptor lacks the ligand-binding domain that enzalutamide and abiraterone act on, and its presence predicts resistance. A degrader or N-terminal binder that removes the whole protein, variants included, would still work; AR-V7 is already measurable in circulating tumour cells.

## Summary

AR-V7 lacks the ligand-binding domain, so enzalutamide and abiraterone cannot act on it, and its presence predicts resistance. Degraders and N-terminal-domain binders that engage full-length AR and its splice variants could restore control. Full-length AR degraders have reached the clinic; variant-competent agents are the unmet need, and AR-V7 status is already measurable in circulating tumour cells.

## Fields

- Kind: Idea
- Last checked: 2026-09-08
- Hypothesis: An AR degrader or N-terminal-domain agent active against AR-V7 produces PSA responses in AR-V7-positive castration-resistant prostate cancer, where the response rate to further AR-pathway inhibition is near zero.
- Rationale: AR-V7 is a well-defined, biomarker-selectable population with a mechanistically obvious unmet need; the degrader modality directly bypasses the missing ligand pocket.
- Proposed test: Phase 1b enriched for AR-V7-positive patients by circulating tumour cell assay, with PSA response rate and paired biopsy AR degradation as endpoints.
- Maturity: preclinical-evidence
- Actor: industry

## Sources

- Bottleneck evidence (The undruggable drivers): Dang et al., Drugging the 'undruggable' cancer targets (Nature Reviews Cancer 2017): https://doi.org/10.1038/nrc.2017.36

## Connected records

- roadmaps: [Prostate cancer roadmap: from Huggins and the discovery that a cancer can depend on a hormone, through the PSA epidemic and what it cost, the androgen receptor drugs, the DNA repair subset and PSMA, to a 2032 registry watch](https://onco.cc/roadmaps/prostate-roadmap/)
- ideas: [Watch for the cancer changing cell type before the biopsy says neuroendocrine, and act on it](https://onco.cc/ideas/idea-prostate-plasticity-surveillance-before-it-is-neuroendocrine/)
- cancers: [Prostate cancer](https://onco.cc/cancers/prostate/)
- technologies: [PROTACs & molecular glues (targeted protein degradation)](https://onco.cc/technologies/protac-degrader/)
- targets: [Androgen receptor](https://onco.cc/targets/androgen-receptor/)
- companies: [Arvinas](https://onco.cc/companies/arvinas/)
- pathways: [Androgen receptor signalling](https://onco.cc/pathways/ar-signaling/)
- bottlenecks: [Acquired resistance to every therapy](https://onco.cc/bottlenecks/b-resistance/), [The undruggable drivers](https://onco.cc/bottlenecks/b-undruggable-targets/)
- key papers: [Androgen receptor in prostate cancer](https://onco.cc/key-papers/paper-androgen-receptor-prostate-endocr-rev-2004/), [Androgen receptor: structure, role in prostate cancer and drug discovery](https://onco.cc/key-papers/paper-androgen-receptor-prostate-acta-pharmacol-sin-2015/), [AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer](https://onco.cc/key-papers/paper-antonarakis-ar-v7-resistance-nejm-2014/), [Drugging the 'undruggable' cancer targets](https://onco.cc/key-papers/paper-dang-nat-rev-cancer/), [Emerging mechanisms of resistance to androgen receptor inhibitors in prostate cancer](https://onco.cc/key-papers/paper-androgen-receptor-prostate-nat-rev-cancer-2015/)

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