title: Distinct Receptor Tyrosine Kinase Subsets Mediate Anti-HER2 Drug Resistance in Breast Cancer.
abstract: Targeted inhibitors of the human epidermal growth factor receptor 2 (HER2), such as trastuzumab and lapatinib, are among the first examples of molecularly targeted cancer therapy and have proven largely effective for the treatment of HER2-positive breast cancers. However, approximately half of those patients either do not respond to these therapies or develop secondary resistance. Although a few signaling pathways have been implicated, a comprehensive understanding of mechanisms underlying HER2 inhibitor drug resistance is still lacking. To address this critical question, we undertook a concerted approach using patient expression data sets, HER2-positive cell lines, and tumor samples biopsied both before and after trastuzumab treatment. Together, these methods revealed that high expression and activation of a specific subset of receptor tyrosine kinases (RTKs) was strongly associated with poor clinical prognosis and the development of resistance. Mechanistically, these RTKs are capable of maintaining downstream signal transduction to promote tumor growth via the suppression of cellular senescence. Consequently, these findings provide the rationale for the design of therapeutic strategies for overcoming drug resistance in breast cancer via combinational inhibition of the limited number of targets from this specific subset of RTKs.
authors.affiliation: From the Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710 and.
authors.forename: Peter B
authors.initials: PB
authors.lastname: Alexander
authors.affiliation: From the Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710 and.
authors.forename: Rui
authors.initials: R
authors.lastname: Chen
authors.affiliation: the Breast Tumor Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.
authors.forename: Chang
authors.initials: C
authors.lastname: Gong
authors.affiliation: From the Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710 and.
authors.forename: Lifeng
authors.initials: L
authors.lastname: Yuan
authors.affiliation: From the Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710 and.
authors.forename: Jeff S
authors.initials: JS
authors.lastname: Jasper
authors.affiliation: From the Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710 and.
authors.forename: Yi
authors.initials: Y
authors.lastname: Ding
authors.affiliation: From the Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710 and.
authors.forename: Geoffrey J
authors.initials: GJ
authors.lastname: Markowitz
authors.affiliation: From the Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710 and.
authors.forename: Pengyuan
authors.initials: P
authors.lastname: Yang
authors.affiliation: From the Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710 and.
authors.forename: Xin
authors.initials: X
authors.lastname: Xu
authors.affiliation: From the Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710 and.
authors.forename: Donald P
authors.initials: DP
authors.lastname: McDonnell
authors.affiliation: the Breast Tumor Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.
authors.forename: Erwei
authors.initials: E
authors.lastname: Song
authors.affiliation: From the Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710 and xiao.fan.wang@duke.edu.
authors.forename: Xiao-Fan
authors.initials: XF
authors.lastname: Wang
mesh_terms: D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D000077341:Lapatinib; D011799:Quinazolines / Q000494:pharmacology*; D018719:Erb-b2 Receptor Tyrosine Kinases; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D000068878:Trastuzumab / Q000494:pharmacology*
chemical_list: D000077341:Lapatinib; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C508053:ERBB2 protein, human
keywords: breast cancer; cellular senescence; drug resistance; human epidermal growth factor receptor 2 (HER2); insulin-like growth factor (IGF); receptor tyrosine kinase; targeted therapy