Investigational fibroblast growth factor receptor 2 antagonists in early phase clinical trials to treat solid tumors

ABSTRACT

Introduction: Fibroblast growth factor receptor 2 (FGFR2) is a highly conserved transmembrane tyrosine kinase receptor. FGFR2 dysregulation occurs in numerous human solid tumors and overexpression is closely associated with tumor progression. FGFR2 has recently been reported as a therapeutic target for cancer. Several targeted therapies are being investigated to disrupt FGFR2 activity; these include multi-target tyrosine kinase inhibitors (TKIs), pan-FGFR targeted TKIs and FGFR2 monoclonal antibodies.

Areas: This review examines FGFR2 regulation and function in cancer and its potential as a target for cancer treatment.

Expert opinion: Highly specific FGFR2 blockers have not yet been developed and moreover, resistance to FGFR2-targeted therapies is a challenge. More sophisticated patient selection strategies would help improve FGFR2-targeted therapies and combination therapy is considered the most promising approach for cancer patients with FGFR2 alterations.

KEYWORDS:

• Fibroblast growth factor receptor 2 (FGFR2)
• solid tumor
• multi-target tyrosine kinase inhibitors (TKIs)
• FGFR-target TKIs
• antibody

Article Highlights

• The fibroblast growth factor receptor 2 (FGFR2) belongs to a family of four typical membrane-bound receptor tyrosine kinases (RTKs) that mediate signaling for FGFs.

• FGFR2 dysregulation, mediated by genetic alterations including FGFR2 amplification, mutation, and fusion, is associated with oncogenesis and can be a potential therapeutic target in cancer.

• Three strategies have been developed to target FGFR2, including multi-target tyrosine kinase inhibitors (TKIs), pan-FGFR targeted TKIs, and FGFR2 monoclonal antibodies.

• The major challenge of FGFR2-targeted treatment is drug resistance which results from factors that include the activation of bypass signaling pathways, the emergence of secondary FGFR alterations, and intratumor heterogeneity.

• Combination therapy is considered the most promising approach for cancers with FGFR2 alterations.

• Compounds specifically targeting FGFR2 are needed and this prompts researchers to further investigate the refined molecular structure and mechanisms of action of activated FGFR2.

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Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose

Additional information

Funding

The research of the authors was funded by National Natural Science Foundation of China U1804281 81771781 81602024