High Mobility Group AT-hook 2: A Biomarker Associated with Resistance to Enzalutamide in Prostate Cancer Cells

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Metastatic prostate cancer (mPCa) poses a significant mortality risk, often driven by resistance to anti-androgen therapies like enzalutamide.
• The transcription factor Snail contributes to this resistance by upregulating full-length AR and AR-V7.
• High Mobility Group AT-hook 2 (HMGA2), a DNA-binding protein, is implicated in cell proliferation and epithelial-mesenchymal transition (EMT), processes relevant to cancer progression.

Purpose of the Study:

• To investigate the role of High Mobility Group AT-hook 2 (HMGA2) in the development of enzalutamide resistance in metastatic prostate cancer (mPCa).
• To determine if HMGA2 expression influences sensitivity to enzalutamide and alisertib.
• To explore the clinical relevance of HMGA2 alterations in mPCa patients.

Main Methods:

• Overexpression of wild-type and truncated HMGA2 variants in LNCaP and 22Rv1 prostate cancer cell lines.
• Assessment of epithelial-mesenchymal transition (EMT) markers and sensitivity to enzalutamide and alisertib.
• Analysis of HMGA2 and AR/AR variant expression in enzalutamide-sensitive and resistant C4-2B cell lines.
• HMGA2 knockdown experiments in resistant cells.
• Clinical data analysis using cBioPortal for HMGA2 and AR alterations in mPCa patients.

Main Results:

• Overexpression of wild-type HMGA2 induced EMT and decreased sensitivity to enzalutamide, but not alisertib.
• Both wild-type and truncated HMGA2 variants reduced sensitivity to enzalutamide.
• HMGA2 overexpression did not affect AR expression levels.
• Enzalutamide-resistant C4-2B cells (C4-2B MDVR) exhibited elevated HMGA2 and AR/AR variant expression and remained sensitive to alisertib.
• HMGA2 knockdown in C4-2B MDVR cells restored sensitivity to both enzalutamide and alisertib without altering AR expression.
• Clinical analysis revealed HMGA2 alterations in 3% of mPCa patients, often associated with enzalutamide, abiraterone, or alisertib treatments, and prevalent in bone, lymph node, and liver metastases.

Conclusions:

• HMGA2 is identified as a potential independent biomarker for enzalutamide resistance in metastatic prostate cancer (mPCa), irrespective of Snail and AR signaling pathways.
• HMGA2 expression levels correlate with resistance to enzalutamide.
• Alisertib presents a potential therapeutic option for mPCa patients whose tumors exhibit HMGA2 expression.