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Screening and Identification of Small Peptides Targeting Fibroblast Growth Factor Receptor2 using a Phage Display Peptide Library
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Targeting the FGF/FGFR axis and its co-alteration allies

Y Uehara1, S Ikeda2, K H Kim3

  • 1Department of Precision Cancer Medicine, Center for Innovative Cancer Treatment, Tokyo Medical and Dental University, Tokyo; Department of Thoracic Oncology and Respiratory Medicine, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan.

ESMO Open
|December 1, 2022
PubMed
Abstract

Insights

Fibroblast growth factor (FGF)/FGF receptor (FGFR) alterations are linked to poorer cancer prognosis and often occur with co-alterations. Combination therapy targeting both cyclin and FGFR pathways shows promise for treating these malignancies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Fibroblast growth factor (FGF)/FGF receptor (FGFR) pathway alterations are implicated in various cancers.
  • Co-occurring genetic alterations (co-alterations) may influence cancer progression and treatment response.
  • Understanding the FGF/FGFR landscape and its co-alterations is crucial for developing targeted therapies.

Purpose of the Study:

  • To analyze the FGF/FGFR and co-alteration cancer landscape.
  • To investigate the prognostic impact of FGF/FGFR alterations and associated co-drivers.
  • To evaluate the efficacy of combination therapies targeting co-altered pathways.

Main Methods:

  • Analysis of FGF/FGFR-altered pathways, prognosis, and co-alterations using cBioPortal (N=7574).
  • Evaluation of therapeutic outcomes in patients treated with FGFR inhibitors at the University of California San Diego Molecular Tumor Board (MTB) (N=16).
  • Comparison of overall survival (OS) between patients with and without FGF/FGFR alterations.

Main Results:

  • Patients with FGF/FGFR alterations had significantly shorter overall survival (OS) compared to those without (23.1 vs. 26.4 months, P=0.038).
  • TP53 (70%), cell cycle (58%), PI3K (55%), and MAPK (65%) were the most frequent co-altered pathways.
  • Combination therapy with a CDK4/6 inhibitor (palbociclib) and an FGFR inhibitor (lenvatinib) resulted in partial responses (PR) in 50% of patients with cyclin pathway co-alterations.

Conclusions:

  • FGF/FGFR alterations are associated with poor prognosis and frequently accompanied by pathogenic co-aberrations.
  • Malignancies with co-alterations in both cyclin and FGFR pathways can be effectively co-targeted.
  • Targeting co-activated cyclin and FGFR pathways with CDK4/6 and FGFR inhibitors demonstrates therapeutic potential.
Keywords:
FGFRcombination therapydrug resistancematched therapyprecision cancer medicinetyrosine kinase inhibitor

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