ZNF397 Loss Triggers TET2-driven Epigenetic Rewiring, Lineage Plasticity, and AR-targeted Therapy Resistance in AR-dependent Cancers

Cancer cells exhibit phenotypical plasticity and epigenetic reprogramming, which allows them to evade lineage-dependent targeted treatments by adopting lineage plasticity. The underlying mechanisms by which cancer cells exploit the epigenetic regulatory machinery to acquire lineage plasticity and therapy resistance remain poorly understood. We identified Zinc Finger Protein 397 (ZNF397) as a bona fide co-activator of the androgen receptor (AR), essential for the transcriptional program governing AR-driven luminal lineage. ZNF397 deficiency facilitates the transition of cancer cell from an AR-driven luminal lineage to a Ten-Eleven Translocation 2 (TET2)-driven lineage plastic state, ultimately promoting resistance to therapies inhibiting AR signaling. Intriguingly, our findings indicate that TET2 inhibitor can eliminate the AR targeted therapies resistance in ZNF397-deficient tumors. These insights uncover a novel mechanism through which prostate and breast cancers acquire lineage plasticity via epigenetic rewiring and offer promising implications for clinical interventions designed to overcome therapy resistance dictated by lineage plasticity. ### Competing Interest Statement P.M. served as a scientific consultant to Accutar Biotechnology, Inc. G.V.R. holds issued and pending patents, which have been licensed to EtiraRx. G.V.R. serves or has served in an advisory role to Bayer, Johnson and Johnson, Myovant, EtiraRx, Amgen, Pfizer, and Astellas. He has or has had grant support from Bayer, EtiraRx, and Johnson and Johnson. C.L.A. serves or has served as a scientific advisor to Novartis, Lilly, Merck, AstraZeneca, Daiichi Sankyo, TAIHO Oncology, Sanofi, OrigiMed, PUMA Biotechnology, Arvinas, and the Susan G. Komen Foundation. He has received grant support from Pfizer, Takeda, and Lilly. T.W. is a scientific co-founder of NightStar Biotechnologies, Inc. A.B.H. receives research grant support from a Breast Cancer Research Foundation/Lilly drug-research collaborative. All other authors declare that they have no competing interests.