Targeting FGFR2 and NOTCH1 Molecular Interactions: Implications for Novel Drug Development in Cancer Therapy

Anna Antonio^*
*Correspondence: Anna Antonio, Department of Pathology, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece, Email:

Introduction

The intricate network of molecular interactions in cancer cells plays a pivotal role in tumour progression, treatment resistance, and metastasis. Among these interactions, the interplay between Fibroblast Growth Factor Receptor 2 (FGFR2) and NOTCH1 has emerged as a critical focus for developing novel cancer therapies. Understanding how these two key signalling pathways interact offers promising avenues for targeted drug development and personalized treatment strategies. Cancer remains one of the most formidable health challenges globally, with molecular interactions within cells often playing critical roles in its development and progression. Among these interactions, those involving Fibroblast Growth Factor Receptor 2 (FGFR2) and NOTCH1 have garnered significant attention. Both FGFR2 and NOTCH1 are crucial signaling molecules that regulate various cellular processes, including proliferation, differentiation and survival. This article delves into the molecular interactions between FGFR2 and NOTCH1, exploring their implications for cancer therapy.

Description

FGFR2, a member of the fibroblast growth factor receptor family, is involved in various cellular processes including proliferation, differentiation, and survival. Aberrant FGFR2 signaling is frequently implicated in a range of cancers, including breast, gastric, and endometrial cancers. FGFR2 activation promotes tumorigenesis by driving oncogenic signaling cascades such as the MAPK/ERK pathway, which enhances cell growth and survival. FGFR2 is a member of the fibroblast growth factor receptor family, which consists of receptor tyrosine kinases. These receptors are activated by binding to fibroblast growth factors (FGFs), leading to receptor dimerization and autophosphorylation. This activation triggers downstream signaling pathways, such as the MAPK/ERK, PI3K/AKT and PLCγ pathways, which are involved in cell proliferation, survival and differentiation [1,2]. Aberrant FGFR2 signaling has been implicated in various cancers, including breast, gastric and lung cancers. Mutations, amplifications and fusions of the FGFR2 gene can lead to its constitutive activation, promoting oncogenesis. Targeting FGFR2 with specific inhibitors has shown promise in clinical trials, highlighting its potential as a therapeutic target [3].

NOTCH1, a transmembrane receptor involved in cell-cell communication, regulates essential processes such as cell fate determination, stem cell maintenance, and apoptosis. In cancer, dysregulated NOTCH1 signaling can contribute to tumor initiation and progression, often through its role in promoting cancer stem cell properties and sustaining aberrant proliferation. The NOTCH signaling pathway is a highly conserved cell signaling system present in most multicellular organisms. NOTCH1, one of the four NOTCH receptors in mammals, is activated by binding to its ligands (Delta-like and Jagged families). Upon ligand binding, NOTCH1 undergoes proteolytic cleavage, releasing the intracellular domain (NICD). The NICD translocates to the nucleus, where it regulates the transcription of target genes involved in cell fate determination, differentiation and proliferation. NOTCH1 plays a dual role in cancer, acting as either an oncogene or a tumor suppressor, depending on the context. In certain cancers, such as T-cell acute lymphoblastic leukemia (T-ALL), NOTCH1 is frequently mutated, leading to its activation and promoting cancer cell survival and proliferation. Conversely, in other cancers, NOTCH1 functions as a tumor suppressor and its loss contributes to tumorigenesis [4].

Emerging evidence suggests a complex interplay between FGFR2 and NOTCH1 signaling pathways. This crosstalk can influence various cellular outcomes and has significant implications for cancer therapy. FGFR2 activation can influence the expression of NOTCH1 ligands, thereby modulating NOTCH1 signaling. Conversely, NOTCH1 signaling can affect the expression of FGFR2 and its downstream targets. Both FGFR2 and NOTCH1 pathways converge on common downstream effectors, such as the MAPK/ERK pathway. Crosstalk at this level can amplify or dampen signaling outputs, affecting cell fate decisions. FGFR2 and NOTCH1 can undergo post-translational modifications, such as phosphorylation and ubiquitination, that affect their stability and activity. Crosstalk between these pathways can modulate these modifications, altering the signaling dynamics.

Understanding the molecular interactions between FGFR2 and NOTCH1 provides new avenues for therapeutic intervention. Several strategies can be envisioned Targeting both FGFR2 and NOTCH1 pathways simultaneously may produce synergistic effects, enhancing therapeutic efficacy and overcoming resistance to single-agent therapies. Identifying biomarkers that reflect the status of FGFR2 and NOTCH1 signaling can guide the selection of patients who are most likely to benefit from targeted therapies. Given the context-dependent roles of FGFR2 and NOTCH1 in cancer, therapies need to be tailored to the specific genetic and molecular landscape of each tumour.

One notable aspect of FGFR2 and NOTCH1 interaction is their combined effect on the tumor microenvironment. Both pathways contribute to the creation of a supportive niche for cancer cells, which can aid in their survival and resistance to conventional therapies. This synergy between FGFR2 and NOTCH1 not only enhances the aggressiveness of tumors but also complicates the development of effective treatments.

Current therapeutic approaches

Several FGFR2 inhibitors are currently in clinical development or have received regulatory approval. These include small molecule tyrosine kinase inhibitors, monoclonal antibodies and FGF ligand traps. Clinical trials have shown promising results, particularly in cancers with FGFR2 alterations [5]. NOTCH1 inhibitors, including γ-secretase inhibitors (GSIs) and monoclonal antibodies targeting NOTCH1 ligands, have been investigated in preclinical and clinical studies. While these inhibitors have shown efficacy in certain cancers, challenges such as toxicity and resistance need to be addressed.

Despite the promising therapeutic potential of targeting FGFR2 and NOTCH1, several challenges remain. Cancer cells can develop resistance to FGFR2 and NOTCH1 inhibitors through various mechanisms, such as secondary mutations and activation of compensatory pathways. Understanding these resistance mechanisms is crucial for developing effective combination therapies. Inhibition of FGFR2 and NOTCH1 signaling can lead to adverse effects, given their roles in normal tissue homeostasis. Strategies to minimize toxicity while maintaining therapeutic efficacy are needed. Reliable biomarkers are essential for patient stratification and monitoring therapeutic responses. Advances in genomics and proteomics hold promise for identifying such biomarkers.

Conclusion

Recent studies have elucidated significant crosstalk between FGFR2 and NOTCH1 pathways. This interaction can occur at multiple levels, including ligand binding, receptor activation, and downstream signaling. For instance, FGFR2 can influence NOTCH1 activity by modulating its expression or altering its activation through shared downstream signaling molecules. Conversely, NOTCH1 signaling can affect FGFR2 expression and its signaling output, creating a feedback loop that can exacerbate tumor growth and resistance to therapy. The intricate molecular interactions between FGFR2 and NOTCH1 have profound implications for cancer therapy. By elucidating the mechanisms of crosstalk and developing targeted interventions, we can improve therapeutic outcomes for patients with cancers driven by aberrant FGFR2 and NOTCH1 signaling. Future research should focus on overcoming the challenges of resistance, toxicity and biomarker identification to fully realize the potential of targeting these pathways in cancer therapy.

Acknowledgement

None.

Conflict of Interest

None.

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