A prostate cancer gastrointestinal transcriptional phenotype may be associated with diminished response to AR-targeted therapy

Aishwarya Subramanian ^1,2, Meng Zhang ^1,2, Marina Sharifi ^3,4

¹Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.
²Department of Radiation Oncology, University of California, San Francisco, San Francisco, CA, USA.
³Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI, USA.
⁴Department of Medicine, University of Wisconsin-Madison, Madison, WI, USA.
⁵Department of Urology, University of California at San Francisco, San Francisco, CA, USA.
⁶Department of Human Oncology, University of Wisconsin-Madison, Madison, WI, USA.
⁷Division of Hematology and Oncology, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA.
⁸William S. Middleton Memorial Veterans' Hospital, Madison, WI, USA.
⁹Department of Pathology, University of California, San Francisco, San Francisco, CA, USA.
¹⁰Department of Epidemiology and Biostatistics, University of California at San Francisco, San Francisco, CA, USA.
¹¹Department of Clinical Sciences Lund, Division of Oncology, Lund University, Lund, Sweden.
¹²Department of Hematology, Oncology and Radiation Physics, Skåne University Hospital, Lund, Sweden.

⁰Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.

Biorxiv : the Preprint Server for Biology +

|

June 19, 2024

View abstract on PubMed

Summary

A gastrointestinal gene expression program (PCa-GI) is prevalent in metastatic castration-resistant prostate cancer (mCRPC) and may indicate resistance to androgen receptor signaling inhibitors (ASI). This phenotype may represent a distinct biological entity with potential for novel therapeutic targets.

Area Of Science

Oncology
Molecular Biology
Genetics

Background

Prostate cancer (PCa) is a heterogeneous disease that can become resistant to treatment, particularly metastatic castration-resistant prostate cancer (mCRPC).
Lineage plasticity, including transformation to neuroendocrine prostate cancer (NEPC) or activation of gastrointestinal (GI) gene expression programs (PCa-GI), is a mechanism of resistance to androgen receptor (AR)-targeting therapies.
The PCa-GI phenotype has been suggested as an alternative resistance mechanism in mCRPC.

Purpose Of The Study

To explore the prevalence and clinical significance of the PCa-GI phenotype in a large cohort of mCRPC patient biopsy samples.
To investigate the association of the PCa-GI phenotype with clinical outcomes, genomic alterations, and molecular pathways.
To determine the differential response to therapies based on PCa-GI status.

Main Methods

Gene expression data from 634 mCRPC samples were analyzed using batch effect correction.
A PCa-GI score was calculated based on 38 previously defined GI-associated genes.
Survival analysis (Kaplan-Meier, Cox regression) and pathway analysis were performed.

Main Results

The PCa-GI score exhibited a bimodal distribution, identifying a distinct subset of tumors (approx. 35%) with high GI expression.
PCa-GI high tumors were not exclusively associated with liver metastases and showed no correlation with proliferation, AR signaling, or NEPC scores, but were associated with MYC amplifications.
Patients with PCa-GI tumors had shorter survival, and a diminished response to androgen receptor signaling inhibitors (ASI) compared to PCa-GI low tumors; FOXA2 signaling was upregulated in PCa-GI high tumors.

Conclusions

The PCa-GI phenotype is prevalent in clinical mCRPC samples and may represent a distinct biological entity.
PCa-GI tumors may exhibit reduced sensitivity to ASI, suggesting a potential strategy for exploring novel therapeutic targets.
Further research into the PCa-GI phenotype could lead to improved treatment strategies for resistant prostate cancer.

Related Concept Videos

Targeted Cancer Therapies

The targeted cancer therapies, also known as “molecular targeted therapies,” take advantage of the molecular and genetic differences between the cancer cells and the normal cells. It needs a thorough understanding of the cancer cells to develop drugs that can target specific molecular aspects that drive the growth, progression, and spread of cancer cells without affecting the growth and survival of other normal cells in the body.
There are several types of targeted therapies against...