Allosteric PI3Kα Inhibition Overcomes On-target Resistance to Orthosteric Inhibitors Mediated by Secondary PIK3CA...

Area of Science:

• Oncology
• Molecular Biology
• Genomics

Background:

• PIK3CA mutations are common in HR-positive breast cancer, with alpelisib approved for treatment.
• Mechanisms of acquired resistance to PI3Kα inhibitors are not fully understood.
• Understanding resistance is crucial for improving treatment strategies.

Purpose of the Study:

• To define the clinical landscape of acquired resistance to PI3Kα inhibitors in advanced breast cancer.
• To identify genomic alterations driving resistance.
• To evaluate novel therapeutic strategies to overcome resistance.

Main Methods:

• Serial liquid biopsies and rapid autopsies were performed on 39 patients with advanced breast cancer.
• Genomic alterations within the PI3K pathway were analyzed.
• The efficacy of a novel allosteric PI3Kα inhibitor (RLY-2608) was assessed.

Main Results:

• 50% of patients acquired genomic alterations in the PI3K pathway, including PTEN loss and AKT1 mutations.
• Novel secondary PIK3CA resistance mutations were identified, altering the inhibitor binding pocket.
• Resistance induced by these mutations was overcome by RLY-2608.

Conclusions:

• Genomic alterations in the PI3K pathway are a major mechanism of acquired resistance to PI3Kα inhibitors.
• Novel PIK3CA resistance mutations emerge and can be targeted.
• Allosteric PI3Kα inhibitors like RLY-2608 show promise in overcoming resistance.