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

Femina Rauf, Fernanda Festa, Jin G. Park, Mitchell Magee, Seron Eaton, Capria Rinaldi, Carlos Morales Betanzos, Laura Gonzalez-Malerva, Joshua Labaer

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Alterations in ERBB family members have been associated with many tumor malignancies. EGFR and ERBB2 have been extensively explored in clinical oncology and several drugs currently target them therapeutically. However, the significance of ERBB4 as a potential therapeutic target remains mostly unexplored, even though ERBB4 is overexpressed or mutated in many solid tumors. Using a unique functional protein microarray platform, we found that ibrutinib inhibits ERBB4 activity in the same nM range as its canonical target, BTK. Cell-based assays revealed that ibrutinib treatment inhibited cell growth and decreased phosphorylation of ERBB4 and downstream targets MEK and ERK in cancer cell lines with high levels of endogenous ERBB4. In vivo, ibrutinib-responsive mouse xenograft tumors showed decreased tumor volumes with ibrutinib treatment. Interestingly, global gene expression comparisons between responsive and non-responsive cells identified a signature featuring the WNT pathway that predicts growth responsiveness to ibrutinib. Non-responsive ERBB4-expressing cell lines featured elevated activity of the WNT pathway, through the overexpression of WNT5A. Moreover, inhibition of WNT5A expression led to an ibrutinib response in non-responsive cell lines. Our data show that inhibiting ERBB4 reduces cell growth in cells that have low WNT5A expression and reveal a link between the ERBB4 and WNT pathways.

Original languageEnglish (US)
Pages (from-to)2237-2250
Number of pages14
JournalOncogene
Volume37
Issue number17
DOIs
StatePublished - Apr 1 2018

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Growth
Neoplasms
Cell Line
Protein Array Analysis
Medical Oncology
Mitogen-Activated Protein Kinase Kinases
Tumor Burden
Heterografts
PCI 32765
Inhibition (Psychology)
Phosphorylation
Gene Expression
Pharmaceutical Preparations
Therapeutics

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

Rauf, F., Festa, F., Park, J. G., Magee, M., Eaton, S., Rinaldi, C., ... Labaer, J. (2018). Ibrutinib inhibition of ERBB4 reduces cell growth in a WNT5A-dependent manner. Oncogene, 37(17), 2237-2250. https://doi.org/10.1038/s41388-017-0079-x
Rauf, Femina ; Festa, Fernanda ; Park, Jin G. ; Magee, Mitchell ; Eaton, Seron ; Rinaldi, Capria ; Betanzos, Carlos Morales ; Gonzalez-Malerva, Laura ; Labaer, Joshua. / Ibrutinib inhibition of ERBB4 reduces cell growth in a WNT5A-dependent manner. In: Oncogene. 2018 ; Vol. 37, No. 17. pp. 2237-2250.
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Rauf, F, Festa, F, Park, JG, Magee, M, Eaton, S, Rinaldi, C, Betanzos, CM, Gonzalez-Malerva, L & Labaer, J 2018, 'Ibrutinib inhibition of ERBB4 reduces cell growth in a WNT5A-dependent manner', Oncogene, vol. 37, no. 17, pp. 2237-2250. https://doi.org/10.1038/s41388-017-0079-x

Ibrutinib inhibition of ERBB4 reduces cell growth in a WNT5A-dependent manner. / Rauf, Femina; Festa, Fernanda; Park, Jin G.; Magee, Mitchell; Eaton, Seron; Rinaldi, Capria; Betanzos, Carlos Morales; Gonzalez-Malerva, Laura; Labaer, Joshua.

In: Oncogene, Vol. 37, No. 17, 01.04.2018, p. 2237-2250.

Research output: Contribution to journalArticle

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AU - Festa, Fernanda

AU - Park, Jin G.

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AU - Eaton, Seron

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AU - Betanzos, Carlos Morales

AU - Gonzalez-Malerva, Laura

AU - Labaer, Joshua

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N2 - Alterations in ERBB family members have been associated with many tumor malignancies. EGFR and ERBB2 have been extensively explored in clinical oncology and several drugs currently target them therapeutically. However, the significance of ERBB4 as a potential therapeutic target remains mostly unexplored, even though ERBB4 is overexpressed or mutated in many solid tumors. Using a unique functional protein microarray platform, we found that ibrutinib inhibits ERBB4 activity in the same nM range as its canonical target, BTK. Cell-based assays revealed that ibrutinib treatment inhibited cell growth and decreased phosphorylation of ERBB4 and downstream targets MEK and ERK in cancer cell lines with high levels of endogenous ERBB4. In vivo, ibrutinib-responsive mouse xenograft tumors showed decreased tumor volumes with ibrutinib treatment. Interestingly, global gene expression comparisons between responsive and non-responsive cells identified a signature featuring the WNT pathway that predicts growth responsiveness to ibrutinib. Non-responsive ERBB4-expressing cell lines featured elevated activity of the WNT pathway, through the overexpression of WNT5A. Moreover, inhibition of WNT5A expression led to an ibrutinib response in non-responsive cell lines. Our data show that inhibiting ERBB4 reduces cell growth in cells that have low WNT5A expression and reveal a link between the ERBB4 and WNT pathways.

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