Ibrutinib inhibition of ERBB4 reduces cell growth in a WNT5A-dependent manner

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Alterations in the ERBB family, including EGFR and ERBB2, are implicated in numerous cancers, with targeted therapies available.
• ERBB4, despite its overexpression and mutation in solid tumors, remains a largely unexplored therapeutic target.

Purpose of the Study:

• To investigate the therapeutic potential of targeting ERBB4.
• To explore the efficacy of ibrutinib against ERBB4 and its downstream signaling pathways.
• To identify predictive biomarkers for ibrutinib response in ERBB4-expressing cancers.

Main Methods:

• Utilized a functional protein microarray to assess ibrutinib's inhibitory activity against ERBB4.
• Conducted cell-based assays to evaluate the impact of ibrutinib on cancer cell growth and signaling.
• Employed mouse xenograft models to study ibrutinib's in vivo anti-tumor effects.
• Performed global gene expression analysis to identify predictive signatures for ibrutinib response.

Main Results:

• Ibrutinib demonstrated potent inhibition of ERBB4 activity in the nanomolar range.
• Ibrutinib treatment reduced cell proliferation and phosphorylation of ERBB4, MEK, and ERK in ERBB4-high cancer cell lines.
• In vivo studies showed significant tumor volume reduction in ibrutinib-responsive xenografts.
• A WNT pathway signature, specifically WNT5A overexpression, predicted non-responsiveness to ibrutinib; inhibiting WNT5A restored sensitivity.

Conclusions:

• Ibrutinib effectively inhibits ERBB4 and reduces cancer cell growth, particularly in contexts of low WNT5A expression.
• The study reveals a significant interplay between the ERBB4 and WNT pathways.
• Targeting ERBB4 with ibrutinib presents a promising therapeutic avenue for specific solid tumors, potentially guided by WNT pathway activity.