Hotspot mutations in HER2 interfaces destabilize structure, causing breast cancer treatment failure

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• HER2-positive breast cancer (BC) often recurs despite targeted therapies like trastuzumab and neratinib.
• Mechanisms of acquired resistance to HER2-targeted therapies remain incompletely understood.

Purpose of the Study:

• To identify specific mutations in the HER2 receptor that confer resistance to HER2-targeted therapies.
• To elucidate the structural and signaling consequences of these identified mutations.

Main Methods:

• Analysis of pathogenic mutations in HER2 dimerization domains II and IV.
• Proximity ligation assays to assess HER2:HER3 interactions.
• Cellular assays (survival, migration) and bioluminescence imaging to evaluate treatment response.
• Assessment of downstream signaling pathways (ERK, AKT).

Main Results:

• Identified mutations G309A, S310Y, and P523S in HER2 dimerization domains II and IV disrupt HER2:HER2 binding.
• Mutations promote HER2:HER3 interactions and a signaling switch from ERK to AKT.
• These mutations confer significant resistance to trastuzumab and neratinib in vitro and in vivo.
• Tucatinib, an FDA-approved HER2 kinase inhibitor, retained efficacy against these resistant mutants.

Conclusions:

• Specific HER2 dimerization domain mutations are novel mechanisms of resistance to trastuzumab and neratinib.
• Targeting HER2 dimerization domains may offer new therapeutic strategies for resistant breast cancer.
• Tucatinib remains a viable treatment option for patients with these resistance mutations.