RB1-deficient prostate tumor growth and metastasis are vulnerable to ferroptosis induction via the E2F/ACSL4 axis

Area of Science:

• Oncology
• Molecular Biology
• Cancer Cell Death Mechanisms

Background:

• RB1 tumor suppressor gene inactivation is frequent in therapy-resistant cancers like prostate cancer, correlating with poor outcomes.
• Developing effective treatments for RB1-deficient cancers remains a significant clinical challenge.

Purpose of the Study:

• To investigate the molecular mechanisms by which RB1 loss influences cancer cell vulnerability.
• To explore ferroptosis as a therapeutic strategy for RB1-deficient malignancies.

Main Methods:

• Analysis of RB1 loss/E2F activation effects on ferroptosis pathways.
• Investigated the role of ACSL4 and its downstream lipid metabolism in ferroptosis.
• Utilized cell line-derived xenografts and genetically engineered mouse models to test in vivo efficacy of GPX4 inhibition.

Main Results:

• RB1 loss/E2F activation sensitizes cancer cells to ferroptosis via ACSL4 upregulation and enrichment of specific phospholipids.
• ACSL4 is identified as a direct E2F target gene crucial for RB1 loss-induced ferroptosis sensitization.
• In vivo treatment with GPX4 inhibitor JKE-1674 suppressed tumor growth, metastasis, and improved survival in RB1-deficient models.

Conclusions:

• A novel RB/E2F/ACSL4 molecular axis regulating ferroptosis is uncovered.
• Targeting ferroptosis with GPX4 inhibitors presents a promising therapeutic avenue for RB1-deficient cancers.