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Lineage plasticity-mediated therapy resistance in prostate cancer
Alexandra M Blee1,2, Haojie Huang1,3,4
1Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
Abstract:
Therapy resistance is a significant challenge for prostate cancer treatment in clinic. Although targeted therapies such as androgen deprivation and androgen receptor (AR) inhibition are effective initially, tumor cells eventually evade these strategies through multiple mechanisms. Lineage reprogramming in response to hormone therapy represents a key mechanism that is increasingly observed. The studies in this area have revealed specific combinations of alterations present in adenocarcinomas that provide cells with the ability to transdifferentiate and perpetuate AR-independent tumor growth after androgen-based therapies. Interestingly, several master regulators have been identified that drive plasticity, some of which also play key roles during development and differentiation of the cell lineages in the normal prostate. Thus, further study of each AR-independent tumor type and understanding underlying mechanisms are warranted to develop combinational therapies that combat lineage plasticity in prostate cancer.
Insights
Prostate cancer cells can evade androgen deprivation therapy by changing their cell type, known as lineage reprogramming. Understanding these mechanisms is crucial for developing new treatments to overcome therapy resistance.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Therapy resistance is a major obstacle in prostate cancer treatment.
- Androgen deprivation and androgen receptor (AR) inhibition therapies are initially effective but tumors develop resistance.
- Lineage reprogramming is an emerging key mechanism of resistance to hormone therapy in prostate cancer.
Purpose of the Study:
- To investigate the mechanisms of AR-independent tumor growth in prostate cancer.
- To identify master regulators driving cell plasticity and lineage reprogramming.
- To provide a basis for developing novel combination therapies against prostate cancer.
Main Methods:
- Analysis of adenocarcinoma alterations driving transdifferentiation.
- Identification of master regulators involved in cell plasticity.
- Study of lineage plasticity in normal prostate development and differentiation.
Main Results:
- Specific genetic alterations in adenocarcinomas facilitate cell transdifferentiation.
- Master regulators driving plasticity have been identified.
- Some regulators identified also play roles in normal prostate cell development.
Conclusions:
- Lineage reprogramming is a critical mechanism for prostate cancer to evade hormone therapy.
- Understanding the identified regulators and mechanisms is essential for future therapeutic strategies.
- Further research is needed to develop combination therapies targeting lineage plasticity and overcoming resistance.
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