Lineage plasticity represents a significant challenge in the treatment of metastatic castration-resistant prostate cancer (mCRPC), characterized by the ability of cancer cells to change from one identity to another. This capacity enables them to evade therapies targeting the androgen receptor (AR).
This adaptability is mirrored in other cancers and is especially problematic in mCRPC with concurrent TP53 and RB1 loss-of-function, where resistance is often linked with abnormal activation of SOX2.1,2 Other than TP53 and RB1, there are also many known lineage plasticity regulators. Beyond these, several regulators of lineage plasticity have been identified, including CHD1 and SYNCRIP.3,4 Loss of these genes triggers significant epigenetic and genomic shifts, facilitating the transition towards identity shifting. Additionally, recent studies have highlighted UBE2J1 and ZNF397 as emerging regulators of AR signaling, indicating their potential roles in driving lineage plasticity.5
The Role of JAK/STAT Signaling:
Our research uncovers that aberrant activation of the JAK/STAT signaling pathway plays a crucial role in mediating lineage plasticity-driven AR targeted therapy resistance, particularly in mCRPC characterized by TP53/RB1-deficiency and SOX2 upregulation.6 We discovered that SOX2 directly regulates JAK/STAT signaling, creating a positive feedback loop that escalates the adaptability of cancer cells and their resistance to therapy. Further, this amplification of the JAK/STAT pathway occurs independently of interferon, typically recognized as the canonical activator of JAK/STAT signaling. This independence indicates that the heightened activity of this pathway stems from the unique genetic and epigenetic framework of tumors rather than from external signaling. Interestingly, JAK/STAT signaling is indispensable for the survival of subclones exhibiting stem-like and multi-lineage transcriptional programs. In contrast, this pathway is less critical for cells already transitioning into neuroendocrine-like lineages.
Strategic Implications for Therapy:
The results underscore the critical role of the JAK/STAT pathway in driving lineage plasticity and highlight the potential benefits of targeting this pathway in overcoming therapy resistance. Disrupting key elements of the JAK/STAT pathway, through either genetic perturbation such as CRISPR knockouts of JAK1 and STAT1, or pharmacological interventions using inhibitors like filgotinib and ruxolitinib, has demonstrated effectiveness in reversing the lineage plasticity. This reversal is significant, as it also reinstates the sensitivity of cancer cells to AR-targeted therapies. These findings offered a promising therapeutic avenue, suggesting that a dual-focused treatment strategy that simultaneously targets lineage plasticity and AR signaling could provide a robust approach to mitigating the complexities introduced by lineage plasticity in cancer treatment.
Conclusion and Future Directions:
The complex interplay of genetic, transcriptional, and signaling layers involved in lineage plasticity in PCa presents significant therapeutic challenges but also new opportunities for intervention. Our study highlights the pivotal role of the JAK/STAT signaling pathway in this context. However, it's important to recognize that the role of JAK/STAT in lineage plasticity is just one piece of a much larger puzzle. There are many other factors, particularly those driving neuroendocrine differentiation, that contribute significantly to the complexity of lineage plasticity. The potential to develop treatments that specifically target these factors and counteract lineage plasticity in PCa is immense. As we deepen our understanding of these diverse mechanisms, we stand on the brink of discovering more innovative and potent therapies to navigate the challenging dynamics of prostate cancer.
Written by: Choushi Wang,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
- Mu, P., Zhang, Z., Benelli, M., Karthaus, W.R., Hoover, E., Chen, C.C., Wongvipat, J., Ku, S.Y., Gao, D., Cao, Z., et al. (2017). SOX2 promotes lineage plasticity and antiandrogen resistance in TP53- and RB1-deficient prostate cancer. Science 355, 84-88. 10.1126/science.aah4307.
- Ku, S.Y., Rosario, S., Wang, Y., Mu, P., Seshadri, M., Goodrich, Z.W., Goodrich, M.M., Labbe, D.P., Gomez, E.C., Wang, J., et al. (2017). Rb1 and Trp53 cooperate to suppress prostate cancer lineage plasticity, metastasis, and antiandrogen resistance. Science 355, 78-83. 10.1126/science.aah4199.
- Zhang, Z., Zhou, C., Li, X., Barnes, S.D., Deng, S., Hoover, E., Chen, C.C., Lee, Y.S., Zhang, Y., Wang, C., et al. (2020). Loss of CHD1 Promotes Heterogeneous Mechanisms of Resistance to AR-Targeted Therapy via Chromatin Dysregulation. Cancer Cell. 10.1016/j.ccell.2020.03.001.
- Li, X., Wang, Y., Deng, S., Zhu, G., Wang, C., Johnson, N.A., Zhang, Z., Tirado, C.R., Xu, Y., Metang, L.A., et al. (2023). Loss of SYNCRIP unleashes APOBEC-driven mutagenesis, tumor heterogeneity, and AR-targeted therapy resistance in prostate cancer. Cancer Cell. 10.1016/j.ccell.2023.06.010.
- Rodriguez Tirado, C., Wang, C., Li, X., Deng, S., Gonzalez, J., Johnson, N.A., Xu, Y., Metang, L.A., Sundar Rajan, M., Yang, Y., et al. (2023). UBE2J1 is the E2 ubiquitin-conjugating enzyme regulating androgen receptor degradation and antiandrogen resistance. Oncogene. 10.1038/s41388-023-02890-5.
- Deng, S., Wang, C., Wang, Y., Xu, Y., Li, X., Johnson, N.A., Mukherji, A., Lo, U.G., Xu, L., Gonzalez, J., et al. (2022). Ectopic JAK-STAT activation enables the transition to a stem-like and multilineage state conferring AR-targeted therapy resistance. Nat Cancer 3, 1071-1087. 10.1038/s43018-022-00431-9.