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Updated: Jun 3, 2025
A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer
Published on: March 6, 2018
Beyond the Horizon: Rethinking Prostate Cancer Treatment Through Innovation and Alternative Strategies
Siddhant Bhoir1,2, Arrigo De Benedetti1
1Department of Biochemistry and Molecular Biology, LSU Health Shreveport, Shreveport, LA 71103, USA.
Abstract:
For nearly a century, fundamental observations that prostate cancer (PCa) cells nearly always require AR stimulation for sustained proliferation have led to a unidirectional quest to abrogate such a pathway. Similarly focused have been efforts to understand AR-driven processes in the context of elevated expression of its target genes, and much less so on products that become overexpressed when AR signaling is suppressed. Treatment with ARSI results in an increased expression of the TLK1B splice variant via a 'translational' derepression driven by the compensatory mTOR activation and consequent activation of the TLK1 > NEK1 > ATR > Chk1 and NEK1 > YAP axes. In due course, this results first in a pro-survival quiescence and then adaptation to ADT and CRPC progression. This constitutes a novel liability for PCa that we have targeted for several years and novel approaches.
Insights
Prostate cancer cells adapt to androgen deprivation therapy by upregulating TLK1B via mTOR signaling. This adaptation promotes survival and resistance, offering a new therapeutic target for advanced prostate cancer.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Prostate cancer (PCa) growth is historically linked to androgen receptor (AR) signaling.
- Therapeutic strategies primarily focus on inhibiting AR signaling.
- Limited understanding exists regarding cellular responses to AR signaling suppression.
Purpose of the Study:
- To investigate molecular mechanisms driving PCa adaptation to AR signaling inhibition.
- To identify novel therapeutic targets in treatment-resistant prostate cancer.
Main Methods:
- Analysis of gene expression changes following AR signaling inhibition.
- Investigation of the role of mammalian target of rapamycin (mTOR) pathway.
- Elucidation of downstream signaling cascades including TLK1B, NEK1, ATR, Chk1, and YAP.
Main Results:
- Androgen Receptor Signaling Inhibitor (ARSI) treatment increases TLK1B expression through mTOR-mediated translational derepression.
- This leads to activation of the TLK1 > NEK1 > ATR > Chk1 and NEK1 > YAP signaling axes.
- These pathways promote cancer cell survival, quiescence, and adaptation to androgen deprivation therapy (ADT), leading to castration-resistant prostate cancer (CRPC).
Conclusions:
- Suppression of AR signaling creates a novel vulnerability in prostate cancer.
- The identified TLK1B-mediated pathway represents a potential therapeutic target for overcoming ADT resistance and CRPC progression.
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