Identification of CDC25 as a Common Therapeutic Target for Triple-Negative Breast Cancer

Area of Science:

• Oncology
• Molecular Biology
• Cancer Therapeutics

Background:

• CDK4/6 inhibitors are effective against RB1-expressing cancer cells but not RB1-deficient cells.
• RB1 loss, often with PTEN and TP53 inactivation, is common in triple-negative breast cancer (TNBC).
• Targeting RB1-deficient cancers, particularly TNBC, remains a significant clinical challenge.

Purpose of the Study:

• To identify novel therapeutic targets for RB1-deficient TNBC.
• To evaluate CDC25 phosphatase as a potential therapeutic target in TNBC.
• To explore synergistic treatment strategies for RB1-deficient TNBC.

Main Methods:

• Performed kinome/phosphatase inhibitor screens on mouse and human TNBC cell lines with specific genetic deficiencies (Rb/p53, Pten/p53, RB1/PTEN/TP53).
• Assessed the efficacy of CDC25 inhibition alone and in combination with CDK inhibitors (CDK1, CDK2, CDK4/6), WEE1 inhibitors, and PI3K inhibitors.
• Evaluated treatment responses in vitro and in vivo using xenotransplantation models.

Main Results:

• Identified CDC25 phosphatase as a common target in RB1-deficient TNBC.
• CDC25 inhibition suppressed the growth of RB1-deficient TNBC cells resistant to CDK4/6 plus CDK2 inhibition.
• Strong synergy was observed between CDC25 and WEE1 inhibitors, and between CDC25 and PI3K inhibitors in suppressing TNBC growth.
• Long-term CDC25 inhibition led to increased PI3K signaling, highlighting the rationale for combined CDC25 and PI3K inhibition.

Conclusions:

• CDC25 phosphatase is a promising therapeutic target for RB1-deficient TNBC.
• Combination therapies involving CDC25 inhibitors, particularly with WEE1 or PI3K inhibitors, demonstrate significant efficacy.
• These findings provide a strong rationale for developing CDC25-based therapies for a broad range of TNBCs, including those with RB1/PTEN/TP53 deficiencies.