Targeting the Chromatin-Modifying Enzyme, KDM5C, Enhances AKT Inhibition Response in ER+ Breast Cancer

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Capivasertib, an AKT inhibitor, combined with fulvestrant shows clinical benefit in PIK3CA/PTEN/AKT-1 altered ER+ breast cancer.
• Understanding resistance and sensitivity mechanisms to capivasertib is crucial for optimizing ER+ BC treatment.

Purpose of the Study:

• To identify genetic modifiers of response to capivasertib in PI3K-AKT pathway altered ER+ breast cancer cells.
• To investigate the role of chromatin regulators, specifically KDM5C, in modulating sensitivity to capivasertib and fulvestrant.

Main Methods:

• Genome-wide CRISPR screen in ER+ BC cell lines with PI3K-AKT pathway alterations.
• Genetic knockout (KO) and pharmacological inhibition of KDM5C.
• RNA-sequencing and epigenetic profiling.
• Assessment of anti-proliferative effects, cell cycle, cell stress, DNA damage, and cell death.

Main Results:

• Loss of chromatin regulators, including KDM5C, significantly increased sensitivity to capivasertib.
• KDM5C inhibition enhanced capivasertib's anti-proliferative effects, both as monotherapy and with fulvestrant, in various resistant ER+ BC models.
• Combined capivasertib and KDM5C KO induced cell stress, DNA damage, and cell death, rather than significantly altering gene transcription.
• Capivasertib and fulvestrant combination enhanced fulvestrant's transcriptional effects.

Conclusions:

• Chromatin regulators play a role in mediating response to capivasertib in ER+ BC.
• Inhibiting KDM5C represents a potential strategy to enhance sensitivity to capivasertib in ER+ BC with specific genetic alterations.
• Targeting chromatin regulators may overcome resistance mechanisms in advanced breast cancer.