Recurrent cancer-associated ERBB4 mutations are transforming and confer resistance to targeted therapies

Area of Science:

• Oncology
• Molecular Biology
• Cancer Genetics

Background:

• Receptor tyrosine kinase ERBB4 (HER4) mutations are implicated in cancer progression and therapeutic resistance.
• Recurrent ERBB4 mutations often occur in critical activation regions or mimic known oncogenic mutations.

Purpose of the Study:

• To investigate the functional impact of cancer-associated ERBB4 mutations.
• To evaluate the oncogenic potential and therapeutic sensitivity of these mutations.

Main Methods:

• Cell-based transformation assays were used to assess oncogenic potential.
• Functional analyses characterized mutation-driven activation, receptor cooperation, and drug sensitivity.
• In vitro and in vivo models evaluated resistance to targeted therapies.

Main Results:

• Over half of the analyzed ERBB4 mutations (11/18) exhibited transforming activity in cell models.
• Potent mutations S303F, E452K, and L798R demonstrated activating properties, cooperated with other ERBB receptors, and were sensitive to neratinib, afatinib, and dacomitinib.
• The S303F mutation, alongside E715K, conferred resistance to osimertinib in EGFR-mutant lung cancer models.

Conclusions:

• Recurrent ERBB4 mutations possess significant oncogenic potential and influence therapeutic responses.
• Clinically available pan-ERBB inhibitors show efficacy against specific ERBB4 mutations.
• These findings support testing pan-ERBB inhibitors for ERBB4-mutated cancers, including in cases of acquired resistance.