PI3K-p110α mediates resistance to HER2-targeted therapy in HER2+, PTEN-deficient breast cancers

Area of Science:

• Oncology
• Molecular Biology
• Cancer Therapeutics

Background:

• HER2 amplification/overexpression (HER2+) is common in breast tumors and often linked to PI3K pathway activation.
• PI3K pathway activation in HER2+ breast cancer is frequently driven by PIK3CA mutations or PTEN loss.
• PTEN loss typically confers sensitivity to p110β inhibitors, while PIK3CA mutations suggest sensitivity to p110α inhibitors.

Purpose of the Study:

• To investigate the role of p110α and p110β isoforms in HER2-positive, PTEN-deficient breast tumors.
• To evaluate the therapeutic potential of combined HER2 and PI3K isoform inhibition in preclinical models.

Main Methods:

• Generated genetic mouse models of breast cancer with concurrent HER2 activation and PTEN loss, with or without p110α or p110β deletion.
• Assessed tumor development and PI3K/AKT signaling in mouse models.
• Evaluated the efficacy of combined HER2, p110α, and p110β inhibition in vitro, in vivo, and in a xenograft model.

Main Results:

• Ablation of p110α, but not p110β, significantly inhibited the development of HER2+/PTEN-null mouse breast tumors.
• p110α was identified as the primary mediator of oncogenic signaling in HER2+/PTEN-deficient human cancers.
• Combined HER2 and p110α inhibition reduced cancer cell growth; adding a p110β inhibitor induced tumor regression in xenografts.

Conclusions:

• p110α plays a critical role in driving oncogenic signaling in HER2+/PTEN-deficient breast tumors.
• p110β conditionally mediates PI3K/AKT signaling, particularly upon HER2 inhibition.
• Combined inhibition of HER2 and p110α/β isoforms represents a promising therapeutic strategy for HER2+, PTEN-deficient breast tumors.