PI3K activation promotes resistance to eribulin in HER2-negative breast cancer

Area of Science:

• Oncology
• Pharmacology
• Molecular Biology

Background:

• Eribulin is a key treatment for advanced/metastatic breast cancer (BC) after prior anthracycline/taxane therapies.
• PIK3CA mutations are linked to poorer chemotherapy response in ER+/HER2- metastatic BC.
• The role of phosphoinositide 3-kinase (PI3K)/AKT pathway mutations in eribulin resistance remains to be fully elucidated.

Purpose of the Study:

• To investigate the association between PI3K/AKT pathway mutations and eribulin resistance in HER2- metastatic BC.
• To evaluate the efficacy of combining PI3K inhibitors with eribulin in overcoming eribulin resistance.

Main Methods:

• Eribulin resistance was assessed in HER2- BC cell lines and patient-derived tumor xenografts.
• Genetic analysis was performed to identify PI3K/AKT pathway mutations in resistant and sensitive models.
• In vitro and in vivo experiments evaluated the impact of PI3K inhibitors on eribulin efficacy.

Main Results:

• 64% of eribulin-resistant HER2- BC xenografts harbored PI3K/AKT pathway mutations (PIK3CA, PIK3R1, AKT1), compared to 17% of sensitive xenografts (P=0.036).
• Eribulin treatment induced AKT phosphorylation in vitro and in patient tumors.
• Co-administration of PI3K inhibitors reversed both primary and acquired eribulin resistance in xenograft models, irrespective of PI3K/AKT alterations or ER status.

Conclusions:

• PI3K pathway activation contributes to primary resistance and early adaptation to eribulin in HER2- BC.
• Combination therapy with PI3K inhibitors and eribulin shows promise for treating HER2- BC patients, potentially overcoming resistance mechanisms.