PD-L1 expression is regulated by ATP-binding of the ERBB3 pseudokinase domain

Area of Science:

• Oncology
• Molecular Biology
• Immunology

Background:

• The regulation of Programmed Death-Ligand 1 (PD-L1) expression in cancer remains incompletely understood.
• Epidermal Growth Factor Receptor (EGFR) family member ERBB3 is a pseudokinase with high ATP-binding affinity.

Purpose of the Study:

• To investigate the role of ERBB3 pseudokinase activity in regulating PD-L1 gene expression in colorectal cancers (CRCs).
• To elucidate the molecular mechanisms linking ERBB3 to PD-L1 regulation.
• To assess the potential of ERBB3 mutations as biomarkers for immune checkpoint therapy response.

Main Methods:

• Utilized genetically engineered mouse models and CRC cell line xenografts to study ERBB3 function.
• Assessed the impact of an ERBB3 ATP-binding inactivation mutant on tumor growth and PD-L1 expression.
• Investigated the signaling pathway involved in ERBB3-mediated PD-L1 regulation, including interferon-gamma (IFN-γ) induction.
• Analyzed the effect of tumor-derived ERBB3 mutations on anti-PD1 antibody therapy response in mouse models.

Main Results:

• ERBB3 ATP-binding inactivation significantly reduced tumorigenicity and xenograft tumor growth in CRC models.
• ERBB3 ATP-binding mutant cells exhibited dramatically reduced IFN-γ-induced PD-L1 expression.
• ERBB3 was found to regulate PD-L1 expression via the IRS1-PI3K-PDK1-RSK-CREB signaling axis, with CREB acting as the key transcription factor.
• Knockin of a tumor-derived ERBB3 mutation sensitized mouse colon cancers to anti-PD1 antibody therapy.

Conclusions:

• ERBB3 pseudokinase activity is a critical regulator of PD-L1 gene expression in colorectal cancers.
• The IRS1-PI3K-PDK1-RSK-CREB pathway mediates ERBB3's regulation of PD-L1.
• ERBB3 mutations represent potential predictive biomarkers for patient response to immune checkpoint inhibitors, particularly anti-PD1 therapy.