title: An AcquiredHER2T798IGatekeeper Mutation Induces Resistance to Neratinib in a Patient with HER2 Mutant-Driven Breast Cancer.
abstract: We report aHER2T798Igatekeeper mutation in a patient withHER2L869R-mutant breast cancer with acquired resistance to neratinib. Laboratory studies suggested thatHER2L869Ris a neratinib-sensitive, gain-of-function mutation that upon dimerization with mutant HER3E928G, also present in the breast cancer, amplifies HER2 signaling. The patient was treated with neratinib and exhibited a sustained partial response. Upon clinical progression,HER2T798Iwas detected in plasma tumor cell-free DNA. Structural modeling of this acquired mutation suggested that the increased bulk of isoleucine in HER2T798Ireduces neratinib binding. Neratinib blocked HER2-mediated signaling and growth in cells expressing HER2L869Rbut not HER2L869R/T798IIn contrast, afatinib and the osimertinib metabolite AZ5104 strongly suppressed HER2L869R/T798I-induced signaling and cell growth. Acquisition of HER2T798Iupon development of resistance to neratinib in a breast cancer with an initial activatingHER2mutation suggestsHER2L869Ris a driver mutation. HER2T798I-mediated neratinib resistance may be overcome by other irreversible HER2 inhibitors like afatinib.Significance:We found an acquiredHER2gatekeeper mutation in a patient withHER2-mutant breast cancer upon clinical progression on neratinib. We speculate thatHER2T798Imay arise as a secondary mutation following response to effective HER2 tyrosine kinase inhibitors (TKI) in other cancers withHER2-activating mutations. This resistance may be overcome by other irreversible HER2 TKIs, such as afatinib.Cancer Discov; 7(6); 575-85. ©2017 AACR.This article is highlighted in the In This Issue feature, p. 539.
authors.affiliation: Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee.|Breast Cancer Research Program, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Ariella B
authors.initials: AB
authors.lastname: Hanker
authors.affiliation: Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Monica Red
authors.initials: MR
authors.lastname: Brewer
authors.affiliation: Department of Biochemistry, Vanderbilt University, Nashville, Tennessee.|Vanderbilt Center for Structural Biology, Vanderbilt University, Nashville, Tennessee.
authors.forename: Jonathan H
authors.initials: JH
authors.lastname: Sheehan
authors.affiliation: Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: James P
authors.initials: JP
authors.lastname: Koch
authors.affiliation: Department of Chemistry, Vanderbilt University, Nashville, Tennessee.
authors.forename: Gregory R
authors.initials: GR
authors.lastname: Sliwoski
authors.affiliation: Guardant Health, Redwood City, California.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Nagy
authors.affiliation: Guardant Health, Redwood City, California.
authors.forename: Richard
authors.initials: R
authors.lastname: Lanman
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Berger
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: David M
authors.initials: DM
authors.lastname: Hyman
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: David B
authors.initials: DB
authors.lastname: Solit
authors.affiliation: Foundation Medicine, Cambridge, Massachusetts.
authors.forename: Jie
authors.initials: J
authors.lastname: He
authors.affiliation: Foundation Medicine, Cambridge, Massachusetts.
authors.forename: Vincent
authors.initials: V
authors.lastname: Miller
authors.affiliation: Puma Biotechnology, Inc., Los Angeles, California.
authors.forename: Richard E
authors.initials: RE
authors.lastname: Cutler
authors.affiliation: Puma Biotechnology, Inc., Los Angeles, California.
authors.forename: Alshad S
authors.initials: AS
authors.lastname: Lalani
authors.affiliation: AstraZeneca Pharmaceuticals, Cambridge, United Kingdom.
authors.forename: Darren
authors.initials: D
authors.lastname: Cross
authors.affiliation: Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee.|Department of Cancer Biology, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Lovly
authors.affiliation: Vanderbilt Center for Structural Biology, Vanderbilt University, Nashville, Tennessee.|Department of Chemistry, Vanderbilt University, Nashville, Tennessee.
authors.forename: Jens
authors.initials: J
authors.lastname: Meiler
authors.affiliation: Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee. carlos.arteaga@vanderbilt.edu.|Breast Cancer Research Program, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee.|Department of Cancer Biology, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Carlos L
authors.initials: CL
authors.lastname: Arteaga
mesh_terms: D000077716:Afatinib; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011799:Quinazolines / Q000494:pharmacology; D011804:Quinolines / Q000627:therapeutic use*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics*
chemical_list: D000077716:Afatinib; D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D011804:Quinolines; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human; C487932:neratinib