FOXA1 and adaptive response determinants to HER2 targeted therapy in TBCRC 036

Area of Science:

• Oncology
• Molecular Biology
• Cancer Research

Background:

• HER2-positive (HER2+) breast cancer treatment relies on HER2/ERBB2 receptor inhibition.
• Resistance to anti-HER2 therapies like trastuzumab, pertuzumab, and lapatinib is common due to adaptive tumor changes.
• Understanding these adaptive mechanisms is critical for improving treatment durability.

Purpose of the Study:

• To characterize transcriptional and epigenetic changes in HER2+ cell lines upon lapatinib inhibition.
• To identify key mediators of adaptive resistance to HER2-targeted therapy.
• To explore novel therapeutic strategies combining HER2 inhibition with targeting adaptive response pathways.

Main Methods:

• RNA sequencing (RNAseq) and ChIP sequencing (ChIPseq) were used to analyze lapatinib-treated HER2+ cell lines.
• Motif analysis identified transcription factor binding sites in responsive genomic regions.
• A 7-day clinical trial examined early pharmacodynamic responses to clinically relevant anti-HER2 drugs.

Main Results:

• FOXA1 was identified as a pioneer transcription factor mediating adaptive responses to lapatinib.
• Combined lapatinib and FOXA1 depletion disrupted enhancer function, impaired HER3 upregulation, and reduced proliferation.
• Clinical trial data showed reduced FOXA1 expression correlated with decreased HER2/HER3 levels and proliferation, alongside increased immune signatures.

Conclusions:

• FOXA1 plays a significant role in adaptive resistance to HER2-targeted therapies.
• Inhibiting FOXA1-mediated adaptive responses in combination with HER2 targeting presents a potential therapeutic strategy.
• The study highlights the importance of the immune response in anti-HER2 antibody therapy and suggests combination approaches.