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أعرض في EDS

FGFR2 Extracellular Domain In-Frame Deletions Are Therapeutically Targetable Genomic Alterations That Function as Oncogenic Drivers in Cholangiocarcinoma.

التفاصيل البيبلوغرافية
العنوان: FGFR2 Extracellular Domain In-Frame Deletions Are Therapeutically Targetable Genomic Alterations That Function as Oncogenic Drivers in Cholangiocarcinoma.
المؤلفون: Cleary JM; Dana-Farber Brigham and Women's Cancer Center, Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts., Raghavan S; Dana-Farber Brigham and Women's Cancer Center, Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts., Wu Q; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts., Li YY; Dana-Farber Brigham and Women's Cancer Center, Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts., Spurr LF; Dana-Farber Brigham and Women's Cancer Center, Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.; Eli and Edythe L Broad Institute of MIT and Harvard, Cambridge, Massachusetts., Gupta HV; Dana-Farber Brigham and Women's Cancer Center, Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts., Rubinson DA; Dana-Farber Brigham and Women's Cancer Center, Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts., Fetter IJ; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts., Hornick JL; Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts., Nowak JA; Dana-Farber Brigham and Women's Cancer Center, Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts., Siravegna G; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts., Goyal L; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts., Shi L; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts., Brais LK; Dana-Farber Brigham and Women's Cancer Center, Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts., Loftus M; Dana-Farber Brigham and Women's Cancer Center, Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts., Shinagare AB; Dana-Farber Brigham and Women's Cancer Center, Department of Radiology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts., Abrams TA; Dana-Farber Brigham and Women's Cancer Center, Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts., Clancy TE; Dana-Farber Brigham and Women's Cancer Center, Department of Surgical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts., Wang J; Dana-Farber Brigham and Women's Cancer Center, Department of Surgical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts., Patel AK; Dana-Farber Brigham and Women's Cancer Center, Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts., Brichory F; Debiopharm International SA, Lausanne, Switzerland., Vaslin Chessex A; Debiopharm International SA, Lausanne, Switzerland., Sullivan RJ; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts., Keller RB; Dana-Farber Brigham and Women's Cancer Center, Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts., Denning S; Dana-Farber Brigham and Women's Cancer Center, Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts., Hill ER; Dana-Farber Brigham and Women's Cancer Center, Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts., Shapiro GI; Dana-Farber Brigham and Women's Cancer Center, Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts., Pokorska-Bocci A; Debiopharm International SA, Lausanne, Switzerland., Zanna C; Debiopharm International SA, Lausanne, Switzerland., Ng K; Dana-Farber Brigham and Women's Cancer Center, Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts., Schrag D; Dana-Farber Brigham and Women's Cancer Center, Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts., Jänne PA; Dana-Farber Brigham and Women's Cancer Center, Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts., Hahn WC; Dana-Farber Brigham and Women's Cancer Center, Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts., Cherniack AD; Dana-Farber Brigham and Women's Cancer Center, Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts., Corcoran RB; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts., Meyerson M; Dana-Farber Brigham and Women's Cancer Center, Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts., Daina A; SIB Swiss Institute of Bioinformatics, Molecular Modeling Group, Lausanne, Switzerland., Zoete V; SIB Swiss Institute of Bioinformatics, Molecular Modeling Group, Lausanne, Switzerland.; University of Lausanne, Department of Fundamental Oncology, Ludwig Lausanne Branch, Lausanne, Switzerland., Bardeesy N; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts. Brian_Wolpin@dfci.harvard.edu Bardeesy.Nabeel@mgh.harvard.edu., Wolpin BM; Dana-Farber Brigham and Women's Cancer Center, Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts. Brian_Wolpin@dfci.harvard.edu Bardeesy.Nabeel@mgh.harvard.edu.
المصدر: Cancer discovery [Cancer Discov] 2021 Oct; Vol. 11 (10), pp. 2488-2505. Date of Electronic Publication: 2021 Apr 29.
نوع المنشور: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: American Association for Cancer Research Country of Publication: United States NLM ID: 101561693 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2159-8290 (Electronic) Linking ISSN: 21598274 NLM ISO Abbreviation: Cancer Discov Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Philadelphia, PA : American Association for Cancer Research
مواضيع طبية MeSH: Bile Duct Neoplasms/*drug therapy , Cholangiocarcinoma/*drug therapy , Protein Kinase Inhibitors/*therapeutic use , Receptor, Fibroblast Growth Factor, Type 2/*genetics, Adolescent ; Adult ; Aged ; Aged, 80 and over ; Bile Duct Neoplasms/genetics ; Bile Duct Neoplasms/pathology ; Cholangiocarcinoma/genetics ; Cholangiocarcinoma/pathology ; Female ; Humans ; Male ; Middle Aged ; Molecular Targeted Therapy ; Receptor, Fibroblast Growth Factor, Type 2/antagonists & inhibitors ; Young Adult
مستخلص: We conducted next-generation DNA sequencing on 335 biliary tract cancers and characterized the genomic landscape by anatomic site within the biliary tree. In addition to frequent FGFR2 fusions among patients with intrahepatic cholangiocarcinoma (IHCC), we identified FGFR2 extracellular domain in-frame deletions (EID) in 5 of 178 (2.8%) patients with IHCC, including two patients with FGFR2 p.H167_N173del. Expression of this FGFR2 EID in NIH3T3 cells resulted in constitutive FGFR2 activation, oncogenic transformation, and sensitivity to FGFR inhibitors. Three patients with FGFR2 EIDs were treated with Debio 1347, an oral FGFR1/2/3 inhibitor, and all showed partial responses. One patient developed an acquired L618F FGFR2 kinase domain mutation at disease progression and experienced a further partial response for 17 months to an irreversible FGFR2 inhibitor, futibatinib. Together, these findings reveal FGFR2 EIDs as an alternative mechanism of FGFR2 activation in IHCC that predicts sensitivity to FGFR inhibitors in the clinic. SIGNIFICANCE: FGFR2 EIDs are transforming genomic alterations that occur predominantly in patients with IHCC. These FGFR2 EIDs are sensitive to FGFR inhibition in vitro , and patients with these alterations benefited from treatment with FGFR inhibitors in the clinic. This article is highlighted in the In This Issue feature, p. 2355 .
(©2021 American Association for Cancer Research.)
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معلومات مُعتمدة: P50 CA127003 United States CA NCI NIH HHS; U54 CA224068 United States CA NCI NIH HHS
المشرفين على المادة: 0 (Protein Kinase Inhibitors)
EC 2.7.10.1 (FGFR2 protein, human)
EC 2.7.10.1 (Receptor, Fibroblast Growth Factor, Type 2)
تواريخ الأحداث: Date Created: 20210430 Date Completed: 20220314 Latest Revision: 20220402
رمز التحديث: 20240628
مُعرف محوري في PubMed: PMC8690974
DOI: 10.1158/2159-8290.CD-20-1669
PMID: 33926920
قاعدة البيانات: MEDLINE
الوصف
تدمد:2159-8290
DOI:10.1158/2159-8290.CD-20-1669