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Targeting FGFR Pathways in Gastrointestinal Cancers: New Frontiers of Treatment
Margherita Ratti1, Elena Orlandi1, Jens Claus Hahne2
1Oncology and Hematology Department, Piacenza General Hospital, Via Taverna 49, 29121 Piacenza, Italy.
Abstract:
In carcinogenesis of the gastrointestinal (GI) tract, the deregulation of fibroblast growth factor receptor (FGFR) signaling plays a critical role. The aberrant activity of this pathway is described in approximately 10% of gastric cancers and its frequency increases in intrahepatic cholangiocarcinomas (iCCAs), with an estimated frequency of 10-16%. Several selective FGFR inhibitors have been developed in the last few years with promising results. For example, targeting the FGFR pathway is now a fundamental part of clinical practice when treating iCCA and many clinical trials are ongoing to test the safety and efficacy of anti-FGFR agents in gastric, colon and pancreatic cancer, with variable results. However, the response rates of anti-FGFR drugs are modest and resistances emerge rapidly, limiting their efficacy and causing disease progression. In this review, we aim to explore the landscape of anti-FGFR inhibitors in relation to GI cancer, with particular focus on selective FGFR inhibitors and drug combinations that may lead to overcoming resistance mechanisms and drug-induced toxicities.
Insights
Fibroblast growth factor receptor (FGFR) inhibitors show promise in gastrointestinal cancers but face modest response rates and rapid resistance. This review explores strategies to overcome these challenges for improved treatment outcomes.
Area of Science:
- Oncology
- Molecular Biology
- Gastroenterology
Background:
- Deregulation of fibroblast growth factor receptor (FGFR) signaling is crucial in gastrointestinal (GI) tract carcinogenesis.
- Aberrant FGFR activity is found in ~10% of gastric cancers and 10-16% of intrahepatic cholangiocarcinomas (iCCAs).
Purpose of the Study:
- To review the current landscape of anti-FGFR inhibitors in GI cancers.
- To focus on selective FGFR inhibitors and combination therapies to overcome resistance and toxicity.
Main Methods:
- Literature review of clinical trials and preclinical studies on FGFR inhibitors in GI cancers.
- Analysis of resistance mechanisms and toxicities associated with FGFR-targeted therapies.
Main Results:
- Selective FGFR inhibitors are established in iCCA treatment, with ongoing trials in other GI cancers.
- Current anti-FGFR therapies exhibit modest response rates and rapid emergence of resistance.
Conclusions:
- Targeting FGFR signaling is a key strategy in GI cancer, but overcoming resistance is critical.
- Combination therapies hold potential for enhancing efficacy and managing toxicities of FGFR inhibitors.
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