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FGFR2 Extracellular Domain In-Frame Deletions Are Therapeutically Targetable Genomic Alterations That Function as

James M Cleary1, Srivatsan Raghavan1, Qibiao Wu2

  • 1Dana-Farber Brigham and Women's Cancer Center, Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.

Cancer Discovery
|April 30, 2021
PubMed

Insights

New genomic alterations, FGFR2 extracellular domain in-frame deletions (EIDs), were found in intrahepatic cholangiocarcinoma (IHCC). These EIDs activate FGFR2, driving cancer growth and responding to FGFR inhibitors.

Area of Science:

  • Genomics
  • Oncology
  • Molecular Biology

Background:

  • Intrahepatic cholangiocarcinoma (IHCC) is a challenging cancer with limited treatment options.
  • Genomic alterations in fibroblast growth factor receptor 2 (FGFR2) are known drivers in a subset of IHCC.
  • Understanding diverse FGFR2 alterations is crucial for targeted therapy development.

Purpose of the Study:

  • To characterize the genomic landscape of biliary tract cancers, focusing on anatomic site variations.
  • To identify novel FGFR2 alterations in IHCC beyond fusions.
  • To evaluate the functional impact and therapeutic sensitivity of newly identified FGFR2 alterations.

Main Methods:

  • Next-generation DNA sequencing of 335 biliary tract cancer samples.
  • Functional assays in NIH3T3 cells to assess oncogenic transformation and pathway activation.
  • Clinical evaluation of patients with FGFR2 alterations treated with FGFR inhibitors.

Main Results:

  • Identified FGFR2 extracellular domain in-frame deletions (EIDs) in 2.8% of IHCC patients.
  • FGFR2 EIDs led to constitutive FGFR2 activation and oncogenic transformation in vitro.
  • Three patients with FGFR2 EIDs achieved partial responses to FGFR inhibitors (Debio 1347).
  • One patient with acquired resistance mutation responded to a second FGFR inhibitor (futibatinib).

Conclusions:

  • FGFR2 EIDs represent an alternative mechanism of FGFR2 activation in IHCC.
  • FGFR2 EIDs predict sensitivity to FGFR inhibitors.
  • Targeting FGFR2 EIDs offers a promising therapeutic strategy for a subset of IHCC patients.

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