What question did this study set out to answer?

To comprehensively profile the molecular and phenotypic diversity driving treatment resistance and disease progression in metastatic castration-resistant prostate cancer.

July 30, 2019Journal of Clinical InvestigationOpen Access

Molecular profiling stratifies diverse phenotypes of treatment-refractory metastatic castration-resistant prostate cancer

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Authors

MLMark P. LabrecqueRevolution Medicines (United States)ICIlsa M. ColemanCape Town HVTN Immunology Laboratory / Hutchinson Centre Research Institute of South Africa LBLisha G. BrownUniversity of Washington

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Implication

Preclinical profiling reveals five distinct molecular subtypes in treatment-resistant metastatic prostate cancer, highlighting androgen receptor and REST regulation in guiding targeted therapies.

Key Points

To comprehensively profile the molecular and phenotypic diversity driving treatment resistance and disease progression in metastatic castration-resistant prostate cancer.
Conducted whole-genome RNA sequencing, gene set enrichment analysis, and immunohistochemistry on clinical metastases and patient-derived xenograft (PDX) lines.
Performed functional knockdown assays targeting the transcription factor REST in cell lines to evaluate drivers of neuroendocrine differentiation.
Identified five distinct phenotypes based on androgen receptor (AR) and neuroendocrine (NE) markers: AR-high, AR-low, amphicrine (co-expressing AR and NE), double-negative, and small cell neuroendocrine tumors.
Demonstrated that loss of REST activity drives the amphicrine phenotype, though REST suppression alone is insufficient to induce full small cell neuroendocrine prostate cancer conversion.
Established a 26-gene transcriptional signature that accurately classifies the five phenotypes and distinguished a double-negative subset with squamous features.

Cite This Study

Labrecque et al. (2019) studied this question.

synapsesocial.com/papers/6a0cd34f291fe4aa6262570f https://doi.org/10.1172/jci128212

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Implication

Preclinical profiling reveals five distinct molecular subtypes in treatment-resistant metastatic prostate cancer, highlighting androgen receptor and REST regulation in guiding targeted therapies.

Molecular profiling stratifies diverse phenotypes of treatment-refractory metastatic castration-resistant prostate cancer

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Implication

Key Points

Cite This Study

Molecular profiling stratifies diverse phenotypes of treatment-refractory metastatic castration-resistant prostate cancer

Discussion

Member takes

Implication

Key Points

Cite This Study

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