HER3 V104 mutations regulate cell signaling, growth, and drug sensitivity in cancer

Area of Science:

• Oncology
• Molecular Biology
• Cancer Genetics

Background:

• Human Epidermal growth factor Receptor 3 (HER3) mutations occur in 2%-10% of cancers.
• Specific HER3 mutations, like V104L and V104M, may influence cancer progression and treatment response.
• Understanding the functional impact of these mutations is crucial for targeted cancer therapies.

Purpose of the Study:

• To investigate the functional consequences of HER3-V104L and HER3-V104M mutations.
• To evaluate the impact of these mutations on cancer cell proliferation and signaling pathways.
• To determine the efficacy of HER2, PI3K, and ERK inhibitors in cancers harboring these HER3 mutations.

Main Methods:

• Utilized CRISPR/Cas9 to create HER3 knockout (HER3KO) HCC1569 breast cancer cells.
• Introduced patient-derived HER3 mutations (V104L, V104M) via lentiviral transduction.
• Assessed protein expression (p-HER3, p-ERK1/2), cell proliferation, and signaling pathway activation (AKT) in response to targeted inhibitors.

Main Results:

• HER3-V104L mutation demonstrated activating effects, increasing p-HER3 and p-ERK1/2 levels and reducing patient survival.
• HER3-V104L expressing cells showed suppressed growth with HER2 inhibitors.
• HER3-V104M mutations were associated with reduced proliferation and sensitivity to ERK inhibitors, with HER3 knockdown abrogating proliferation.

Conclusions:

• The HER3-V104L mutation is clinically relevant, promoting cancer growth and indicating poorer survival.
• Both HER3-V104L and HER3-V104M mutations influence cellular responses to HER2, PI3K, and ERK inhibitors.
• Targeting HER3 signaling pathways, particularly ERK, offers potential therapeutic strategies for cancers with these specific mutations.