title: HER2-Overexpressing Breast Cancers Amplify FGFR Signaling upon Acquisition of Resistance to Dual Therapeutic Blockade of HER2.
abstract: Purpose:Dual blockade of HER2 with trastuzumab and lapatinib or pertuzumab has been shown to be superior to single-agent trastuzumab. However, a significant fraction of HER2-overexpressing (HER2+) breast cancers escape from these drug combinations. In this study, we sought to discover the mechanisms of acquired resistance to the combination of lapatinib + trastuzumab.Experimental Design:HER2+BT474 xenografts were treated with lapatinib + trastuzumab long-term until resistance developed. Potential mechanisms of acquired resistance were evaluated in lapatinib + trastuzumab-resistant (LTR) tumors by targeted capture next-generation sequencing.In vitroexperiments were performed to corroborate these findings, and a novel drug combination was tested against LTR xenografts. Gene expression and copy-number analyses were performed to corroborate our findings in clinical samples.Results:LTR tumors exhibited an increase inFGF3/4/19copy number, together with an increase in FGFR phosphorylation, marked stromal changes in the tumor microenvironment, and reduced tumor uptake of lapatinib. Stimulation of BT474 cells with FGF4 promoted resistance to lapatinib + trastuzumabin vitroTreatment with FGFR tyrosine kinase inhibitors reversed these changes and overcame resistance to lapatinib + trastuzumab. High expression ofFGFR1correlated with a statistically shorter progression-free survival in patients with HER2+early breast cancer treated with adjuvant trastuzumab. Finally,FGFR1and/orFGF3gene amplification correlated with a lower pathologic complete response in patients with HER2+early breast cancer treated with neoadjuvant anti-HER2 therapy.Conclusions:Amplification of FGFR signaling promotes resistance to HER2 inhibition, which can be diminished by the combination of HER2 and FGFR inhibitors.Clin Cancer Res; 23(15); 4323-34. ©2017 AACR.
authors.affiliation: Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee.|Breast Cancer Program, Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee.
authors.forename: Ariella B
authors.initials: AB
authors.lastname: Hanker
authors.affiliation: Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee.
authors.forename: Joan T
authors.initials: JT
authors.lastname: Garrett
authors.affiliation: Breast Cancer Program, Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee.
authors.forename: Mónica Valeria
authors.initials: MV
authors.lastname: Estrada
authors.affiliation: Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee.
authors.forename: Preston D
authors.initials: PD
authors.lastname: Moore
authors.affiliation: Breast Cancer Program, Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee.
authors.forename: Paula González
authors.initials: PG
authors.lastname: Ericsson
authors.affiliation: Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee.
authors.forename: James P
authors.initials: JP
authors.lastname: Koch
authors.affiliation: Prometheus Laboratories, San Diego, California.
authors.forename: Emma
authors.initials: E
authors.lastname: Langley
authors.affiliation: Prometheus Laboratories, San Diego, California.
authors.forename: Sharat
authors.initials: S
authors.lastname: Singh
authors.affiliation: Prometheus Laboratories, San Diego, California.
authors.forename: Phillip S
authors.initials: PS
authors.lastname: Kim
authors.affiliation: Foundation Medicine, Cambridge, Massachusetts.
authors.forename: Garrett M
authors.initials: GM
authors.lastname: Frampton
authors.affiliation: Foundation Medicine, Cambridge, Massachusetts.
authors.forename: Eric
authors.initials: E
authors.lastname: Sanford
authors.affiliation: Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee.
authors.forename: Philip
authors.initials: P
authors.lastname: Owens
authors.affiliation: Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Becker
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, Research Triangle Park, North Carolina.
authors.forename: M Reid
authors.initials: MR
authors.lastname: Groseclose
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, Research Triangle Park, North Carolina.
authors.forename: Stephen
authors.initials: S
authors.lastname: Castellino
authors.affiliation: Department of Oncology, Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: Heikki
authors.initials: H
authors.lastname: Joensuu
authors.affiliation: Department of Gynecology, University of Ulm, Ulm, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Huober
authors.affiliation: Novartis Pharmaceuticals, Basel, Switzerland.
authors.forename: Jan C
authors.initials: JC
authors.lastname: Brase
authors.affiliation: Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Samira
authors.initials: S
authors.lastname: Majjaj
authors.affiliation: Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Brohée
authors.affiliation: Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: David
authors.initials: D
authors.lastname: Venet
authors.affiliation: Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: David
authors.initials: D
authors.lastname: Brown
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: José
authors.initials: J
authors.lastname: Baselga
authors.affiliation: Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Martine
authors.initials: M
authors.lastname: Piccart
authors.affiliation: Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Christos
authors.initials: C
authors.lastname: Sotiriou
authors.affiliation: Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee. carlos.arteaga@vanderbilt.edu.|Breast Cancer Program, Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee.|Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee.
authors.forename: Carlos L
authors.initials: CL
authors.lastname: Arteaga
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D005260:Female; D051518:Fibroblast Growth Factor 3 / Q000037:antagonists & inhibitors / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D000077341:Lapatinib; D051379:Mice; D020360:Neoadjuvant Therapy / Q000009:adverse effects; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D011799:Quinazolines / Q000008:administration & dosage; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics*; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000037:antagonists & inhibitors / Q000235:genetics*; D000068878:Trastuzumab / Q000008:administration & dosage; D023041:Xenograft Model Antitumor Assays
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D051518:Fibroblast Growth Factor 3; D000077341:Lapatinib; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D051496:Receptor, Fibroblast Growth Factor, Type 1; D000068878:Trastuzumab; C496444:FGF3 protein, human; C508053:ERBB2 protein, human; C496348:FGFR1 protein, human; C485206:pertuzumab