title: Receptor tyrosine kinase ERBB4 mediates acquired resistance to ERBB2 inhibitors in breast cancer cells.
abstract: Approximately 25% of breast cancers overexpress and depend on the receptor tyrosine kinase ERBB2, one of 4 ERBB family members. Targeted therapies directed against ERBB2 have been developed and used clinically, but many patients continue to develop resistance to such therapies. Although much effort has been focused on elucidating the mechanisms of acquired resistance to ERBB2-targeted therapies, the involvement of ERBB4 remains elusive and controversial. We demonstrate that genetic ablation of ERBB4, but not ERBB1-3, led to apoptosis in lapatinib-resistant cells, suggesting that the efficacy of pan-ERBB inhibitors was, at least in part, mediated by the inhibition of ERBB4. Moreover, ERBB4 was upregulated at the protein level in ERBB2+ breast cancer cell lines selected for acquired lapatinib resistance in vitro and in MMTV-Neu mice following prolonged lapatinib treatment. Knockdown of ERBB4 caused a decrease in AKT phosphorylation in resistant cells but not in sensitive cells, suggesting that ERBB4 activated the PI3K/AKT pathway in lapatinib-resistant cells. Importantly, ERBB4 knockdown triggered apoptosis not only in lapatinib-resistant cells but also in trastuzumab-resistant cells. Our results suggest that although ERBB4 is dispensable for naïve ERBB2+ breast cancer cells, it may play a key role in the survival of ERBB2+ cancer cells after they develop resistance to ERBB2 inhibitors, lapatinib and trastuzumab.
authors.affiliation: a Department of Pharmacology and Toxicology.
authors.forename: Kaleigh
authors.initials: K
authors.lastname: Canfield
authors.forename: Jiaqi
authors.initials: J
authors.lastname: Li
authors.forename: Owen M
authors.initials: OM
authors.lastname: Wilkins
authors.forename: Meghan M
authors.initials: MM
authors.lastname: Morrison
authors.forename: Matthew
authors.initials: M
authors.lastname: Ung
authors.forename: Wendy
authors.initials: W
authors.lastname: Wells
authors.forename: Charlotte R
authors.initials: CR
authors.lastname: Williams
authors.forename: Karen T
authors.initials: KT
authors.lastname: Liby
authors.forename: Detlef
authors.initials: D
authors.lastname: Vullhorst
authors.forename: Andres
authors.initials: A
authors.lastname: Buonanno
authors.forename: Huizhong
authors.initials: H
authors.lastname: Hu
authors.forename: Rachel
authors.initials: R
authors.lastname: Schiff
authors.forename: Rebecca S
authors.initials: RS
authors.lastname: Cook
authors.forename: Manabu
authors.initials: M
authors.lastname: Kurokawa
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D055785:Gene Knockdown Techniques; D000077341:Lapatinib; D051379:Mice; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors*; D066247:Receptor, ErbB-4 / Q000235:genetics / Q000378:metabolism*; D000068878:Trastuzumab
chemical_list: D000077341:Lapatinib; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D066247:Receptor, ErbB-4; D000068878:Trastuzumab; C524056:Erbb2 protein, mouse; C587690:Erbb4 protein, mouse
keywords: EGFR; EGFR, epidermal growth factor receptor; ERK, extracellular regulated kinase; FGFR, fibroblast growth factor receptor; HER, human epidermal growth factor receptor; HER2; HER3; HER4; Herceptin; MTS, 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium; PI3K, phosphatidylinositol-4,5-bisphosphate 3-kinase; Q-VD-OPh, quinolyl-valyl-O-methylaspartyl-[2,6-difluoro-phenoxy]-methyl ketone; RTK, receptor tyrosine kinase