Targeting ATR and PI3Kα Pathways Promotes Ferroptosis in PIK3CA-Wildtype Platinum-Resistant Endometrial Cancer.

Area of Science:

• Oncology
• Molecular Biology
• Cancer Therapeutics

Background:

• Platinum resistance is a major hurdle in endometrial cancer (EC) treatment.
• Tumors often evade apoptosis, necessitating alternative cell death strategies.
• Ferroptosis, a distinct cell death pathway, presents a potential therapeutic target.

Purpose of the Study:

• To investigate the efficacy of combined ATR and PI3Kα inhibition in platinum-resistant EC.
• To determine if this combination induces cell death through apoptosis or ferroptosis.
• To explore the role of PIK3CA mutation status in treatment response.

Main Methods:

• Utilized a panel of EC cell lines with varying PIK3CA mutation status and platinum sensitivity.
• Administered camonsertib (ATR inhibitor) and inavolisib (PI3Kα inhibitor) as monotherapy and combination.
• Assessed cell death mechanisms using DNA damage, apoptosis, and ferroptosis markers.

Main Results:

• Dual ATR and PI3Kα inhibition demonstrated synergistic cytotoxicity in all tested EC cell lines.
• Treatment induced genotype-specific cell death: apoptosis in PIK3CA-mutant cells and ferroptosis in PIK3CA-wildtype cells.
• Efficacy was independent of platinum sensitivity or microsatellite stability.

Conclusions:

• Combined ATR and PI3Kα inhibition is a viable genotype-informed strategy for platinum-resistant EC.
• PIK3CA mutation status influences the cell death pathway, suggesting its potential as a predictive biomarker.
• This approach offers a novel therapeutic avenue for patient stratification in clinical trials.