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Published on: January 22, 2018
Clinical Developments and Challenges in Treating FGFR2-Driven Gastric Cancer
David K Lau1,2,3,4, Jack P Collin1,2, John M Mariadason1,2
1Olivia Newton-John Cancer Research Institute, Heidelberg, VIC 3084, Australia.
Abstract:
Recent advances in the treatment of gastric cancer (GC) with chemotherapy, immunotherapy, anti-angiogenic therapy and targeted therapies have yielded some improvement in survival outcomes; however, metastatic GC remains a lethal malignancy and amongst the leading causes of cancer-related mortality worldwide. Importantly, the ongoing molecular characterisation of GCs continues to uncover potentially actionable molecular targets. Among these, aberrant FGFR2-driven signalling, predominantly arising from FGFR2 amplification, occurs in approximately 3-11% of GCs. However, whilst several inhibitors of FGFR have been clinically tested to-date, there are currently no approved FGFR-directed therapies for GC. In this review, we summarise the significance of FGFR2 as an actionable therapeutic target in GC, examine the recent pre-clinical and clinical data supporting the use of small-molecule inhibitors, antibody-based therapies, as well as novel approaches such as proteolysis-targeting chimeras (PROTACs) for targeting FGFR2 in these tumours, and discuss the ongoing challenges and opportunities associated with their clinical development.
Insights
Gastric cancer (GC) remains deadly, but FGFR2 amplification presents a target. This review explores FGFR2-targeted therapies, including inhibitors and PROTACs, for treating advanced GC.
Area of Science:
- Oncology
- Molecular Biology
- Drug Development
Background:
- Metastatic gastric cancer (GC) has poor survival outcomes despite advances in treatment.
- Aberrant FGFR2 signaling, often due to FGFR2 amplification, is found in 3-11% of GCs.
- Currently, no approved therapies specifically target FGFR2 in GC.
Purpose of the Study:
- To review the significance of FGFR2 as a therapeutic target in GC.
- To examine pre-clinical and clinical data for FGFR2-directed therapies.
- To discuss challenges and opportunities in developing FGFR2-targeted treatments for GC.
Main Methods:
- Literature review of pre-clinical and clinical studies.
- Analysis of data on FGFR2 amplification in gastric cancer.
- Evaluation of various therapeutic strategies targeting FGFR2.
Main Results:
- FGFR2 amplification is a key driver in a subset of GC patients.
- Small-molecule inhibitors, antibody-based therapies, and PROTACs show promise for FGFR2 targeting.
- Clinical development of FGFR2-directed therapies for GC is ongoing.
Conclusions:
- FGFR2 represents a significant actionable target for GC treatment.
- Multiple therapeutic modalities are being investigated to target FGFR2 in GC.
- Further clinical development is crucial to overcome challenges and realize the potential of FGFR2-targeted therapies.
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