title: Truncated ErbB2 expressed in tumor cell nuclei contributes to acquired therapeutic resistance to ErbB2 kinase inhibitors.
abstract: ErbB2 tyrosine kinase inhibitors (TKI) block tyrosine autophosphorylation and activation of the full-length transmembrane ErbB2 receptor (p185(ErbB2)). In addition to p185(ErbB2), truncated forms of ErbB2 exist in breast cancer cell lines and clinical tumors. The contribution of these truncated forms, specifically those expressed in tumor cell nuclei, to the development of therapeutic resistance to ErbB2 TKIs has not been previously shown. Here, we show that expression of a 95-kDa tyrosine phosphorylated form of ErbB2, herein referred to as p95L (lapatinib-induced p95) was increased in ErbB2(+) breast cancer cells treated with potent ErbB2 TKIs (lapatinib, GW2974). Expressed in tumor cell nuclei, tyrosine phosphorylation of p95L was resistant to inhibition by ErbB2 TKIs. Furthermore, the expression of p95L was increased in ErbB2(+) breast cancer models of acquired therapeutic resistance to lapatinib that mimic the clinical setting. Pretreatment with proteasome inhibitors blocked p95L induction in response to ErbB2 TKIs, implicating the role of the proteasome in the regulation of p95L expression. In addition, tyrosine phosphorylated C-terminal fragments of ErbB2, generated by alternate initiation of translation and similar in molecular weight to p95L, were expressed in tumor cell nuclei, where they too were resistant to inhibition by ErbB2 TKIs. When expressed in the nuclei of lapatinib-sensitive ErbB2(+) breast cancer cells, truncated ErbB2 rendered cells resistant to lapatinib-induced apoptosis. Elucidating the function of nuclear, truncated forms of ErbB2, and developing therapeutic strategies to block their expression and/or activation may enhance the clinical efficacy of ErbB2 TKIs.
authors.affiliation: Duke Comprehensive Cancer Research Center, Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA. Wenle.Xia@duke.edu
authors.forename: Wenle
authors.initials: W
authors.lastname: Xia
authors.forename: Zuguo
authors.initials: Z
authors.lastname: Liu
authors.forename: Rongrong
authors.initials: R
authors.lastname: Zong
authors.forename: Leihua
authors.initials: L
authors.lastname: Liu
authors.forename: Sumin
authors.initials: S
authors.lastname: Zhao
authors.forename: Sarah S
authors.initials: SS
authors.lastname: Bacus
authors.forename: Yubin
authors.initials: Y
authors.lastname: Mao
authors.forename: Jia
authors.initials: J
authors.lastname: He
authors.forename: Julia D
authors.initials: JD
authors.lastname: Wulfkuhle
authors.forename: Emanuel F
authors.initials: EF
authors.lastname: Petricoin
authors.forename: Takuya
authors.initials: T
authors.lastname: Osada
authors.forename: Xiao-Yi
authors.initials: XY
authors.lastname: Yang
authors.forename: Zachary C
authors.initials: ZC
authors.lastname: Hartman
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Clay
authors.forename: Kimberly L
authors.initials: KL
authors.lastname: Blackwell
authors.forename: Herbert K
authors.initials: HK
authors.lastname: Lyerly
authors.forename: Neil L
authors.initials: NL
authors.lastname: Spector
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D020690:GTPase-Activating Proteins / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D000077341:Lapatinib; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008954:Models, Biological; D010766:Phosphorylation / Q000187:drug effects; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D020690:GTPase-Activating Proteins; D000077341:Lapatinib; D046988:Proteasome Endopeptidase Complex; D061988:Proteasome Inhibitors; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; C430213:GIT2 protein, human