Exploring the Role of FGFR1 as a Therapeutic Target Among Patients With MCL

Narendranath Epperla, MD, MS, The Ohio State University, Columbus, Ohio, discusses the current research on fibroblast growth factor receptor-1 (FGFR1) as an up-and-coming and viable therapeutic target for treating patients with mantle cell lymphoma (MCL). 

Transcript: 

Hello everyone. I'm Naren Epperla from Ohio State University, and it is my pleasure today to discuss the role of FGFR and the consequence of inhibiting FGFR1 in mantle cell lymphoma. 

As we all know, the advent of [Bruton’s tyrosine kinase] (BTK) inhibitors a decade ago revolutionized the therapeutic landscape of mantle cell lymphoma. It only improved for the next few years with the advent of newer covalent BTK inhibitors, and more recently, non-covalent BTK inhibitors. In the past 3 years, the availability of cellular therapies, CAR T-cell therapy in specific, has further improved upon the outcomes of patients with mantle cell lymphoma, and more recently the bispecific antibodies have continued to show a similar trend.

Despite all these advances, there are still a substantial number of patients who cannot receive CAR T-cell therapy, be it due to age, comorbidities, or due to poor social support. Additionally, [among] patients who progress following CAR T-cell therapy, the outcomes are poor. Hence, it is important to have newer targeted agents that can provide further therapeutic options for these patients. 

This study was conducted to identify a novel regulator that contributes to the proliferation and survival of mantle cell lymphoma. Unifying the transcriptomics of various factors such as tumor microenvironment, drug resistance, and relapse in MCL patients, we identified FGFR1 as a novel upregulated gene. FGFR1 activation is a known driver in various malignant conditions, both solids as well as hematological tumors. Here, we show that FGFR1 overexpression in mantle cell lymphoma in preclinical models correlated with poor survival. This was independently validated in 3 other preclinical models, which were [the] Rosenwald cohort, Morin cohort, and Young cohort, essentially showing a similar outcome wherein the patients who had high FGFR1 expression and were treated with multi-agent chemotherapy had poor outcomes.

FGFR1 activation can happen through various mechanisms including ligand dependent and ligand independent mechanisms. In addition, we also show that FGFR1 expression can be regulated by stromal cells, thus postulating that both intrinsic and extrinsic factors contribute to FGFR1 overexpression and its activity in mantle cell lymphoma. Functionally, genetic ablation of FGFR1 or pharmacological targeting with small molecule inhibitors that target FGFR1 can induce cell cycle arrest, cell death in vitro and reduced tumor formation, and improve survival in vivo. We also show that EZH2 is downregulated upon FGFR1 loss or inhibition in mantle cell lymphoma cell lines. This observation was pretty much in line with the previous studies that demonstrated that FGFR1-mediated EZH2 regulation was primarily through post-transcriptional regulation.

Our results also indicate an intricate regulation of KDM2B and EZH2 to regulate the repression of  CDKN1C in an FGFR-dependent manner. And this is important because as we all know, cell cycle dysregulation is a hallmark of mantle cell lymphoma. In this disease, overexpression of CDK4 and cyclin D1 promotes the expression of E2F target genes triggering the cells to the replicator phase. 

Our results indicate that loss of FGFR1 in MCL causes a high percentage of G1 cells due to the upregulation of cell-dependent kinase inhibitor C, also known as CDKN1C, and subsequent loss of proliferate to signature gene and E2F1 target genes that are needed to progress through the S-phase. In summary, our findings indicate the CDKN1C binding to E2F1 in MCL cells may be a repressor of E2F1-mediated transactivation. Furthermore, our data show upregulation of CDKN1C in ibrutinib-resistant mantle cells upon loss of FGFR1. Plus, our data here shows that FGFR1 signaling contributes to the suppression of CDKN1C via epigenetic regulation in MCL and may contribute to ibrutinib resistance.

Why is this important? How do we put this into context in the clinical realm? It's important because what we have seen and shown in our study is that FGFR1 is an important and novel therapeutic target that can be studied in this condition. 

We have already started to work on a clinical trial with a small molecule inhibitor targeting FGFR1 in relapsed/refractory mantle cell lymphoma. I'm hoping that in the future, once we have the results, we will learn more about the drug itself and the mechanisms of resistance as well as probably additional biomarkers that will portent a superior response to that small molecule inhibitor targeting the FGFR1. 

Source: 

Sircar A, Singh S, Zijun XM, et al. Exploiting the fibroblast growth factor receptor-1 vulnerability to therapeutically restrict the MYC-EZH2-CDKN1C axis-driven proliferation in mantle cell lymphoma. Leukemia. Published online August 19, 2023. doi: 10.1038/s41375-023-02006-8