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Loss of CHD1 Promotes Heterogeneous Mechanisms of Resistance to AR-Targeted Therapy via Chromatin Dysregulation - Beyond the Abstract

The advancement of targeted cancer therapies has markedly changed cancer treatment, offering more personalized and efficient solutions. However, the varied responses among patients with identical oncogenic drivers and tumor histology signal intricate resistance mechanisms. This is notably true in metastatic castration-resistant prostate cancer (CRPC), where overcoming resistance to androgen receptor (AR)-targeted therapies, such as abiraterone, enzalutamide, and apalutamide, presents a big challenge.1 Despite progress, resistance arises through multiple ways, including reactivation of AR signaling, activation of alternative transcription factors like the glucocorticoid receptor (GR), and lineage plasticity, which shifts to AR-independent growth driven by the loss of TP53 and RB1.2-4

To identify genomic elements affecting metastatic prostate cancer's sensitivity to antiandrogen therapy, a comprehensive in vivo study using a shRNA library targeting 730 genes frequently deleted in prostate cancer was conducted. CHD1 loss was identified as a critical factor contributing to antiandrogen resistance through mechanisms beyond AR signaling reactivation, fostering lineage plasticity that enables cancer cells to evade AR dependency.5 Further investigation of integrated RNA-Seq and ATAC-Seq analyses revealed substantial transcriptional and chromatin accessibility shifts following CHD1 depletion, underscoring CHD1's role in preserving lineage-specific gene expression. An integrative approach identified 22 transcription factors (TFs) that could drive enzalutamide resistance post-CHD1 loss and chromatin remodeling. Functional screenings singled out four TFs—NR3C1, POU3F2, TBX2, and NR2F1—as key players in the resistance mechanism, highlighting a complex interaction between chromatin dynamics, TF activity, and therapy resistance, and suggesting new avenues to combat enzalutamide resistance in CHD1-deficient prostate cancer.

Clinically, low CHD1 mRNA levels correlate with shorter progression-free survival in patients treated with enzalutamide or abiraterone, indicating potential predictive value for therapeutic outcomes. Moreover, GR, as one of the four transcription factors encoded proteins, plays a crucial role in prostate cancer dynamics. GR inhibition has shown promise in reversing enzalutamide resistance in CHD1-deficient tumors, highlighting the importance of targeting altered chromatin and transcriptional landscapes.

The elucidation of CHD1's role in conferring resistance to antiandrogen therapies in metastatic prostate cancer underscores a pivotal shift in our approach to overcoming therapeutic resistance. By uncovering the intricate dynamics between chromatin remodeling and transcription factor activity, this study not only enhances our understanding of the molecular underpinnings of drug resistance but also paves the way for novel therapeutic strategies. Future research will delve into the molecular pathways affected by CHD1 loss, aiming to develop predictive biomarkers for therapy response and innovative treatments that target the resultant transcriptional reprogramming. The complexity of resistance in CRPC, often through AR signaling restoration, underlines the need for strategies that target AR degradation pathways.6 Resistance through lineage plasticity7-9 and CHD1-mediated chromatin remodeling represent significant AR-independent resistance pathways. Additionally, genomic mutagenesis10 and the tumor microenvironment11 play critical roles in resistance. Future therapeutic strategies should, therefore, integrate approaches that target these diverse mechanisms to improve outcomes for CRPC patients.

Written by: Xiaoling Li,1 Ping Mu1,2,3

  1. Department of Molecular Biology, University of Southwestern Medical Center, Dallas, Texas, USA
  2. Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, USA
  3. Hamon Center for Regenerative Science and Medicine, UT Southwestern Medical Center, Dallas, USA

References:

  1. Blatt, E. B. et al. Overcoming oncogene addiction in breast and prostate cancers: a comparative mechanistic overview. Endocrine-Related Cancer 28, R31--R46 (2021). https://doi.org/10.1530/erc-20-0272 , pmid = 33263560
  2. Mu, P. et al. SOX2 promotes lineage plasticity and antiandrogen resistance in TP53- and RB1-deficient prostate cancer. Science 355, 84-88 (2017). https://doi.org/10.1126/science.aah4307
  3. Ku, S. Y. et al. Rb1 and Trp53 cooperate to suppress prostate cancer lineage plasticity, metastasis, and antiandrogen resistance. Science 355, 78 83 (2017). https://doi.org/10.1126/science.aah4199 , pmid = 28059767
  4. Wet, L. d. et al. SOX2 mediates metabolic reprogramming of prostate cancer cells. Oncogene, 1--13 (2022). https://doi.org/10.1038/s41388-021-02157-x , pmid = 35067686
  5. Zhang, Z. et al. Loss of CHD1 Promotes Heterogeneous Mechanisms of Resistance to AR-Targeted Therapy via Chromatin Dysregulation. Cancer Cell 37, 584-598 e511 (2020). https://doi.org/10.1016/j.ccell.2020.03.001
  6. Rodriguez Tirado, C. et al. UBE2J1 is the E2 ubiquitin-conjugating enzyme regulating androgen receptor degradation and antiandrogen resistance. Oncogene 43, 265-280 (2024). https://doi.org/10.1038/s41388-023-02890-5
  7. Deng, S. et al. Ectopic JAK-STAT activation enables the transition to a stem-like and multilineage state conferring AR-targeted therapy resistance. Nat Cancer 3, 1071-1087 (2022). https://doi.org/10.1038/s43018-022-00431-9
  8. Xu, Y. et al. ZNF397 Deficiency Triggers TET2-driven Lineage Plasticity and AR-Targeted Therapy Resistance in Prostate Cancer. Cancer Discov (2024). https://doi.org/10.1158/2159-8290.CD-23-0539
  9. Lo, U. G. et al. The driver role of JAK-STAT signalling in cancer stemness capabilities leading to new therapeutic strategies for therapy- and castration-resistant prostate cancer. Clin Transl Med 12, e978 (2022). https://doi.org/10.1002/ctm2.978
  10. Li, X. et al. Loss of SYNCRIP unleashes APOBEC-driven mutagenesis, tumor heterogeneity, and AR-targeted therapy resistance in prostate cancer. Cancer Cell 41, 1427-1449 e1412 (2023). https://doi.org/10.1016/j.ccell.2023.06.010
  11. Li, X. & Mu, P. The Critical Interplay of CAF Plasticity and Resistance in Prostate Cancer. Cancer Res 83, 2990-2992 (2023). https://doi.org/10.1158/0008-5472.CAN-23-2260
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