title: Polyclonal SecondaryFGFR2Mutations Drive Acquired Resistance to FGFR Inhibition in Patients with FGFR2 Fusion-Positive Cholangiocarcinoma.
abstract: Genetic alterations in the fibroblast growth factor receptor (FGFR) pathway are promising therapeutic targets in many cancers, including intrahepatic cholangiocarcinoma (ICC). The FGFR inhibitor BGJ398 displayed encouraging efficacy in patients with FGFR2 fusion-positive ICC in a phase II trial, but the durability of response was limited in some patients. Here, we report the molecular basis for acquired resistance to BGJ398 in three patients via integrative genomic characterization of cell-free circulating tumor DNA (cfDNA), primary tumors, and metastases. Serial analysis of cfDNA demonstrated multiple recurrent point mutations in theFGFR2kinase domain at progression. Accordingly, biopsy of post-progression lesions and rapid autopsy revealed marked inter- and intralesional heterogeneity, with differentFGFR2mutations in individual resistant clones. Molecular modeling andin vitrostudies indicated that each mutation led to BGJ398 resistance and was surmountable by structurally distinct FGFR inhibitors. Thus, polyclonal secondaryFGFR2mutations represent an important clinical resistance mechanism that may guide the development of future therapeutic strategies.Significance:We report the first genetic mechanisms of clinical acquired resistance to FGFR inhibition in patients with FGFR2 fusion-positive ICC. Our findings can inform future strategies for detecting resistance mechanisms and inducing more durable remissions in ICC and in the wide variety of cancers where the FGFR pathway is being explored as a therapeutic target.Cancer Discov; 7(3); 252-63. ©2016 AACR.See related commentary by Smyth et al., p. 248This article is highlighted in the In This Issue feature, p. 235.
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Lipika
authors.initials: L
authors.lastname: Goyal
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Supriya K
authors.initials: SK
authors.lastname: Saha
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Leah Y
authors.initials: LY
authors.lastname: Liu
authors.affiliation: Candiolo Cancer Institute-FPO, IRCCS, Candiolo, Torino, Italy.|Department of Oncology, University of Torino, Torino, Italy.|Fondazione Italiana per la Ricerca sul Cancro (FIRC) Institute of Molecular Oncology (IFOM), Milano, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Siravegna
authors.affiliation: Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts.
authors.forename: Ignaty
authors.initials: I
authors.lastname: Leshchiner
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Leanne G
authors.initials: LG
authors.lastname: Ahronian
authors.affiliation: Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Jochen K
authors.initials: JK
authors.lastname: Lennerz
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Phuong
authors.initials: P
authors.lastname: Vu
authors.affiliation: Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Vikram
authors.initials: V
authors.lastname: Deshpande
authors.affiliation: Department of Radiology, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Avinash
authors.initials: A
authors.lastname: Kambadakone
authors.affiliation: Candiolo Cancer Institute-FPO, IRCCS, Candiolo, Torino, Italy.
authors.forename: Benedetta
authors.initials: B
authors.lastname: Mussolin
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Reyes
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Laura
authors.initials: L
authors.lastname: Henderson
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Jiaoyuan Elisabeth
authors.initials: JE
authors.lastname: Sun
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Emily E
authors.initials: EE
authors.lastname: Van Seventer
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Gurski
authors.affiliation: Novartis Institutes for BioMedical Research, Oncology Translational Research, Basel, Switzerland.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Baltschukat
authors.affiliation: Novartis Institutes for BioMedical Research, Oncology Translational Research, Basel, Switzerland.
authors.forename: Barbara
authors.initials: B
authors.lastname: Schacher-Engstler
authors.affiliation: Novartis Institutes for BioMedical Research, Oncology Translational Research, Basel, Switzerland.
authors.forename: Louise
authors.initials: L
authors.lastname: Barys
authors.affiliation: Novartis Institutes for BioMedical Research, Oncology Translational Research, Basel, Switzerland.
authors.forename: Christelle
authors.initials: C
authors.lastname: Stamm
authors.affiliation: Novartis Institutes for BioMedical Research, Global Discovery Chemistry, Basel, Switzerland.
authors.forename: Pascal
authors.initials: P
authors.lastname: Furet
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: David P
authors.initials: DP
authors.lastname: Ryan
authors.affiliation: Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: James R
authors.initials: JR
authors.lastname: Stone
authors.affiliation: Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: A John
authors.initials: AJ
authors.lastname: Iafrate
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts.|Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts.
authors.forename: Gad
authors.initials: G
authors.lastname: Getz
authors.affiliation: Novartis Institutes for BioMedical Research, Oncology Translational Research, Basel, Switzerland.
authors.forename: Diana Graus
authors.initials: DG
authors.lastname: Porta
authors.affiliation: Novartis Institutes for BioMedical Research, Oncology Translational Research, Basel, Switzerland.
authors.forename: Ralph
authors.initials: R
authors.lastname: Tiedt
authors.affiliation: Candiolo Cancer Institute-FPO, IRCCS, Candiolo, Torino, Italy.|Department of Oncology, University of Torino, Torino, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Bardelli
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Dejan
authors.initials: D
authors.lastname: Juric
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts. azhu@partners.org nbardeesy@partners.org rbcorcoran@partners.org.
authors.forename: Ryan B
authors.initials: RB
authors.lastname: Corcoran
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts. azhu@partners.org nbardeesy@partners.org rbcorcoran@partners.org.
authors.forename: Nabeel
authors.initials: N
authors.lastname: Bardeesy
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts. azhu@partners.org nbardeesy@partners.org rbcorcoran@partners.org.
authors.forename: Andrew X
authors.initials: AX
authors.lastname: Zhu
mesh_terms: D000328:Adult; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001650:Bile Duct Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D018797:Cell Cycle Proteins; D018281:Cholangiocarcinoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000074141:Circulating Tumor DNA / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D050939:Gene Fusion; D006801:Humans; D008297:Male; D026901:Membrane Transport Proteins; D008875:Middle Aged; D009154:Mutation; D010671:Phenylurea Compounds / Q000627:therapeutic use*; D011743:Pyrimidines / Q000627:therapeutic use*; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics*; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000737:chemistry / Q000378:metabolism; D035582:Transcription Factor TFIIIA / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D000074141:Circulating Tumor DNA; D026901:Membrane Transport Proteins; C409460:OPTN protein, human; D010671:Phenylurea Compounds; D011743:Pyrimidines; D035582:Transcription Factor TFIIIA; C568950:infigratinib; C496353:FGFR2 protein, human; C496365:FGFR3 protein, human; D051497:Receptor, Fibroblast Growth Factor, Type 2; D051498:Receptor, Fibroblast Growth Factor, Type 3