Our investigation was motivated by a pressing clinical challenge: despite advances in targeted therapies, many cancers, particularly metastatic castration-resistant prostate cancer (mCRPC), inevitably develop resistance. This resistance not only curtails the effectiveness of treatment but also limits options for patients, urging the need for novel therapeutic targets and strategies.
Our focus turned to the role of tumor mutational burden and heterogeneity, which are known to fuel resistance to targeted therapies. We were particularly intrigued by the APOBEC family of cytidine deaminases, implicated in the mutational signatures of most human cancers. APOBEC proteins are a double-edged sword; they play a vital role in innate immunity but, when dysregulated, contribute to genomic instability and cancer progression.8,9 Our study aimed to decode how prostate cancer cells hijack the APOBEC-mediated mutagenesis machinery to promote tumor heterogeneity and, consequently, therapy resistance. A critical discovery of our study was the identification of SYNCRIP (synaptotagmin-binding, cytoplasmic RNA-interacting protein) as a key regulator that suppresses APOBEC-driven mutagenesis in prostate cancer.10 The loss of SYNCRIP in prostate cancer cells markedly enhances APOBEC3B activity, leading to a surge in DNA mutations, including in genes crucial for the development of resistance to AR-targeted therapies such as FOXA1, EP300, and the AR gene itself.
Through comprehensive genomic and transcriptomic analyses, we identified eight key genes that APOBEC3B mutates, which are crucial for the development of AR-targeted therapy resistance. This list includes prominent genes such as BRD7, CBX8, EP300, FOXA1, HDAC5, HSF4, STAT3, and AR itself. The mutations in these genes, driven by APOBEC3B, activate alternative signaling pathways that reduce the tumor’s dependency on AR signaling, facilitating resistance. The study’s exploration of the genetic and transcriptomic landscapes of SYNCRIP-deficient prostate cancer cells provides valuable insights into the dynamics of tumor evolution and the emergence of therapy-resistant clones. The detailed mapping of mutational patterns and their impact on cell behavior and treatment response highlights the complexity of cancer progression and the adaptability of tumor cells in the face of therapeutic pressure.
In our study, we embarked on a comprehensive exploration to quantify intratumoral heterogeneity (ITH) in prostate cancer, leveraging both genetic and transcriptomic data. We observed that the ITH scores in wild-type cells initially rose with acute treatment with enzalutamide but declined upon prolonged treatment, suggesting a selection process favoring a subset of resistant cells. In stark contrast, SYNCRIP-deficient cells exhibited a consistent increase in ITH scores under both acute and prolonged treatment, underscoring the role of continuous APOBEC-driven mutagenesis in fostering new resistant cell populations and enhancing tumor heterogeneity.
Through unsupervised Leiden clustering of cellular populations from both wild-type and SYNCRIP-deficient samples, we identified distinct clusters demonstrating the varied evolutionary paths of resistance development. Particularly with SYNCRIP-deficient cells, certain clusters expanded over time, labeled as “prolonged winners,” while others, despite initially expanding, were eventually outcompeted, highlighting the dynamic landscape of therapy resistance. Notably, high levels of APOBEC-driven mutagenesis were linked to these “winner” clusters, reinforcing the pivotal role of APOBEC enzymes in driving resistance through enhanced tumor heterogeneity. Our evolutionary trajectory analysis further unveiled the dominance of specific resistant subclones, particularly those with FOXA1 mutations, in SYNCRIP-deficient cells. These findings suggest that mutations in key resistance drivers, fueled by APOBEC mutagenesis, are crucial for the development and maintenance of therapy resistance.
The journey of our research is far from over. The implications of our findings extend beyond prostate cancer, suggesting that similar mechanisms might be at play in other cancers characterized by high mutational burdens and heterogeneity. As we continue to explore the role of APOBEC proteins and the impact of SYNCRIP deficiency, our goal remains to develop innovative therapeutic strategies that can outsmart cancer’s adaptability, offering hope for more effective treatments in the future. Our findings highlight the potential of targeting APOBEC3B and its associated pathways as a strategic approach to combat therapy resistance. Clinical correlations from our study reveal that patients with higher loads of APOBEC-signature mutations experienced quicker progression to therapy resistance and poorer outcomes, emphasizing the significance of APOBEC-driven mutagenesis in patient prognoses.
In conclusion, our study not only advances our understanding of the molecular mechanisms driving therapy resistance in prostate cancer but also opens new avenues for therapeutic intervention. By elucidating the critical role of APOBEC-driven mutagenesis and the suppressive function of SYNCRIP, we offer a fresh perspective on combating resistance, laying the groundwork for future innovations in cancer therapy.
Written by: Xiaoling Li,1 Ping Mu1,2,3
- Department of Molecular Biology, University of Southwestern Medical Center, Dallas, Texas, USA
- Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, USA
- Hamon Center for Regenerative Science and Medicine, UT Southwestern Medical Center, Dallas, USA
- 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).
- 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).
- Xu, Y. et al. ZNF397 Deficiency Triggers TET2-driven Lineage Plasticity and AR-Targeted Therapy Resistance in Prostate Cancer. Cancer Discov (2024).
- Rodriguez Tirado, C. et al. UBE2J1 is the E2 ubiquitin-conjugating enzyme regulating androgen receptor degradation and antiandrogen resistance. Oncogene 43, 265-280 (2024).
- Blatt, E. B. et al. Overcoming oncogene addiction in breast and prostate cancers: a comparative mechanistic overview. Endocrine-Related Cancer 28, R31--R46 (2021).
- Li, X. & Mu, P. The Critical Interplay of CAF Plasticity and Resistance in Prostate Cancer. Cancer Res 83, 2990-2992 (2023).
- Wet, L. d. et al. SOX2 mediates metabolic reprogramming of prostate cancer cells. Oncogene, 1--13 (2022).
- Swanton, C., McGranahan, N., Starrett, G. J. & Harris, R. S. APOBEC Enzymes: Mutagenic Fuel for Cancer Evolution and Heterogeneity. Cancer Discovery 5, 704--712 (2015).
- Burns, M. B. et al. APOBEC3B is an enzymatic source of mutation in breast cancer. Nature 494, 366 (2013).
- 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).
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Loss of SYNCRIP Unleashes APOBEC-Driven Mutagenesis, Tumor Heterogeneity and AR-Targeted Therapy Resistance in Prostate Cancer - Ping Mu