Actionable Activating Oncogenic ERBB2/HER2 Transmembrane and Juxtamembrane Domain Mutations

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Deregulated human epidermal growth factor receptor 2 (HER2) signaling drives various cancers.
• HER2 is a validated therapeutic target for numerous approved anti-cancer drugs.

Purpose of the Study:

• To identify and characterize novel activating mutations in the HER2 transmembrane domain (TMD) and juxtamembrane domain (JMD).
• To investigate the functional mechanisms of these HER2 mutations and their response to targeted therapies.

Main Methods:

• Analysis of 111,176 patient tumors to identify recurrent HER2 mutations.
• Saturation mutagenesis screening and testing of patient-derived mutations.
• Structural modeling and biochemical assays to determine the mechanism of activation.
• Evaluation of patient-derived HER2 mutants against anti-HER2 antibodies and kinase inhibitors.

Main Results:

• Recurrent activating mutations in HER2 TMD and JMD, including G660D, R678Q, E693K, and Q709L, were identified.
• These mutations enhance HER2 activity by improving dimer interfaces or stabilizing activating conformations.
• The G660D mutation specifically utilizes asymmetric kinase dimerization for activation.
• Both anti-HER2 antibodies and small-molecule kinase inhibitors effectively inhibited the activity of these novel HER2 mutants.
• A patient with germline HER2 G660D-mutant lung cancer exhibited a significant clinical response to HER2-targeted therapy.

Conclusions:

• Novel activating mutations in the HER2 TMD/JMD represent a new class of oncogenic drivers.
• These mutations remain susceptible to established HER2-targeted therapies, including antibodies and kinase inhibitors.
• Targeting these specific HER2 mutations offers a promising therapeutic strategy for a subset of cancer patients.