title: HER family kinase domain mutations promote tumor progression and can predict response to treatment in human breast cancer.
abstract: Resistance to HER2-targeted therapies remains a major obstacle in the treatment of HER2-overexpressing breast cancer. Understanding the molecular pathways that contribute to the development of drug resistance is needed to improve the clinical utility of novel agents, and to predict the success of targeted personalized therapy based on tumor-specific mutations. Little is known about the clinical significance of HER family mutations in breast cancer. Because mutations within HER1/EGFR are predictive of response to tyrosine kinase inhibitors (TKI) in lung cancer, we investigated whether mutations in HER family kinase domains are predictive of response to targeted therapy in HER2-overexpressing breast cancer. We sequenced the HER family kinase domains from 76 HER2-overexpressing invasive carcinomas and identified 12 missense variants. Patients whose tumors carried any of these mutations did not respond to HER2 directed therapy in the metastatic setting. We developed mutant cell lines and used structural analyses to determine whether changes in protein conformation could explain the lack of response to therapy. We also functionally studied all HER2 mutants and showed that they conferred an aggressive phenotype and altered effects of the TKI lapatinib. Our data demonstrate that mutations in the finely tuned HER kinase domains play a critical function in breast cancer progression and may serve as prognostic and predictive markers.
authors.affiliation: Departments of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Delphine R
authors.initials: DR
authors.lastname: Boulbes
authors.affiliation: Departments of Biochemistry & Molecular Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Departments of Center for Biomolecular Structure and Function, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Division of Biological and Environmental Sciences and Engineering, Computational Bioscience Research Center (CBRC), King Abdullah University of Science and Technology (KAUST), Thuwal, Saudi Arabia.
authors.forename: Stefan T
authors.initials: ST
authors.lastname: Arold
authors.affiliation: Departments of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Gaurav B
authors.initials: GB
authors.lastname: Chauhan
authors.affiliation: Departments of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Korina V
authors.initials: KV
authors.lastname: Blachno
authors.affiliation: Departments of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Nanfu
authors.initials: N
authors.lastname: Deng
authors.affiliation: Graduate Institute of Cancer Biology and Center for Molecular Medicine, China Medical University Hospital, Taichung, 404 Taiwan.
authors.forename: Wei-Chao
authors.initials: WC
authors.lastname: Chang
authors.affiliation: Departments of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Quanri
authors.initials: Q
authors.lastname: Jin
authors.affiliation: Departments of Molecular & Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Tzu-Hsuan
authors.initials: TH
authors.lastname: Huang
authors.affiliation: Departments of Molecular & Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Jung-Mao
authors.initials: JM
authors.lastname: Hsu
authors.affiliation: Departments of Molecular & Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Samuel W
authors.initials: SW
authors.lastname: Brady
authors.affiliation: Departments of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Chandra
authors.initials: C
authors.lastname: Bartholomeusz
authors.affiliation: Departments of Biochemistry & Molecular Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Departments of Center for Biomolecular Structure and Function, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; School of Molecular and Cell Biology, University of Leeds, Leeds LS2 9jT, UK.
authors.forename: John E
authors.initials: JE
authors.lastname: Ladbury
authors.affiliation: Myriad Genetics, Salt Lake City, UT 84108, USA.
authors.forename: Steve
authors.initials: S
authors.lastname: Stone
authors.affiliation: Departments of Molecular & Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Dihua
authors.initials: D
authors.lastname: Yu
authors.affiliation: Departments of Molecular & Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Mien-Chie
authors.initials: MC
authors.lastname: Hung
authors.affiliation: Laura and Isaac Perlmutter Cancer Center, New York University Langone Medical Center, 160 E. 34th Street, New York, NY 10016, USA. Electronic address: francisco.esteva@nyumc.org.
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Esteva
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology*; D045744:Cell Line, Tumor; D019295:Computational Biology; D018450:Disease Progression; D066246:ErbB Receptors / Q000737:chemistry* / Q000235:genetics*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D006801:Humans; D000077341:Lapatinib; D008819:Mice, Nude; D050505:Mutant Proteins / Q000737:chemistry; D009154:Mutation / Q000235:genetics*; D010641:Phenotype; D010766:Phosphorylation / Q000187:drug effects; D011379:Prognosis; D017434:Protein Structure, Tertiary; D011799:Quinazolines / Q000494:pharmacology; D016896:Treatment Outcome
chemical_list: D050505:Mutant Proteins; D011799:Quinazolines; D000077341:Lapatinib; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: Biomarker; Drug resistance; HER family mutation; Kinase domain; Lapatinib