Abstract 5332: Targeting CDK2 in estrogen receptor-positive/RB-deficient breast cancer

作者：Chang‐Ching Lin, Pamela Luna, Khushi Ahuja, Dan Ye, Yisheng Fang, Alec Trub, John Bisi, Jay C. Strum, Patrick J. Roberts, Jeon Lee, Ariella B. Hanker, Carlos L. Arteaga · 发表于：Cancer Research · 年份：2025 · DOI：10.1158/1538-7445.am2025-5332 · 被引用次数：1 · 研究领域：Cancer-related Molecular Pathways、Advanced Breast Cancer Therapies、HER2/EGFR in Cancer Research

Abstract The estrogen receptor-positive (ER+) subtype continues to be the leading cause of breast cancer-related mortality worldwide. Although CDK4/6 inhibitors (CDK4/6i) have extended survival of patients with ER+ breast cancer, resistance to these therapies is inevitable. RB1 loss-of-function alterations are a well-established mechanism of resistance to CDK4/6i, occurring in approximately 10% of ER+ breast cancer patients who progress on CDK4/6i. With the broad use of CDK4/6i as the standard treatment, the population of patients with ER+/RB-deficient breast cancer is expected to rise, highlighting an urgent need for effective targeted therapies and therapeutic strategies for this drug-resistant subtype. Using a genome-wide CRISPR screen in ER+ RB1 knockout (RBKO) T47D breast cancer cells, we identified CDK2 as an essential gene. Additionally, analysis of the DepMap dataset further confirmed CDK2 as a top essential gene in cancer cells with low RB1 mRNA expression, suggesting an RB-independent role for CDK2 and its potential as a therapeutic target in cancers with RB deficiency. Supporting this hypothesis, siRNA-mediated silencing of CDK2 (siCDK2) in MCF7 RBKO cells and in lung (H596 and H1155), prostate (Du-145), and triple-negative breast (MDA-MB-468) cancer cells harboring somatic RB1 mutations or deletions led to the accumulation of cells in the G1 phase and a reduction of cells in the S phase, indicating an overall delay in cell cycle progression. Similarly, treatment o...