Mechanisms of Efficacy of the FGFR1–3 Inhibitor AZD4547 in Pediatric Solid Tumor Models

Phanhthilath, Nikki; Hakim, Sara; Su, Catherine K.; Liu, Andrea J.; Subramonian, Divya; Lesperance, Jacqueline; Zage, Peter E.

doi:10.1007/s10637-020-00933-2

Cited by 8 publications

(6 citation statements)

References 72 publications

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“…On the other hand, in FGFR1 N546K overexpressing cells, treatment with AZD4547 alone lead to an increase of phospho-AKT and phospho-STAT3 levels. These ndings further support that AZD4547 treatment by targeting FGFR1 can induce resistance mechanisms [70][71][72][73][74][75] .…”

Section: Discussionsupporting

confidence: 64%

FGFR1 is a Potential Therapeutic Target in Neuroblastoma

Cimmino

Montella

Tirelli

et al. 2022

Preprint

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Background: FGFR1 regulates cell-cell adhesion and extracellular matrix architecture and acts as oncogene in several cancers. Potential cancer driver mutations of FGFR1 occur in neuroblastoma NB, a neural crest-derived pediatric tumor arising in sympathetic nervous system but so far, they have not been studied experimentally. We investigated the driver-oncogene role of FGFR1 and the implication of N546K mutation in therapy-resistance in NB cells.Methods: Public datasets were used to predict the correlation of FGFR1 expression with NB clinical outcomes. Whole genome sequencing data of 19 paired diagnostic and relapse NB samples were used to find somatic mutations. In NB cell lines, silencing and transient overexpression of FGFR1 by short hairpin RNA were performed to evaluate the effect of the found mutation by cell growth, invasion and cologenicity assays. HEK293, SHSY5Y and SKNBE2 were selected to investigate subcellular wildtype and mutated protein localization. FGFR1 inhibitor (AZD4547), alone or in combination with PI3K inhibitor (GDC0941), was used to rescue malignant phenotypes induced by overexpression of FGFR1 wildtype and mutated protein.Results: High FGFR1 expression correlated with low relapse-free survival in two independent NB gene expression datasets. In addition, we found the somatic mutation N546K, the most recurrent point mutation of FGFR1 in all cancers and already reported in NB, in one out of 19 matched primary and recurrent tumors. Loss of FGFR1 function attenuated invasion and cologenicity in NB cells, whereas FGFR1 overexpression enhanced oncogenicity. The overexpression of FGFR1N546K protein showed a higher nuclear localization compared to wildtype protein and increased cellular invasion and cologenicity. Moreover, N546K mutation caused the failure in response to treatment with FGFR1 inhibitor by activation of ERK, STAT3 and AKT pathways. The combination of FGFR1 and PI3K pathway inhibitors was effective in reducing the invasive and colonigenic ability of cells overexpressing FGFR1 mutated protein.Conclusion: FGFR1 is an actionable driver oncogene in NB and a promising therapy may consist in targeting FGFR1 mutations in patients with therapy-resistant NB.

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Section: Discussionsupporting

confidence: 64%

FGFR1 is a Potential Therapeutic Target in Neuroblastoma

Cimmino

Montella

Tirelli

et al. 2022

Preprint

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“…Through integrating hundreds of cancer cell lines' drug screen information, we identified some drugs that could target the molecular features of S1/S2 subtype patients. Interestingly, the drugs estimated for S1 patients were mainly associated with anti-angiogenic and anti-fibrotic activities, such as AZD4547, Foretinib, and Nintedanib [ 69 , 97 , 98 ]. In contrast, drugs that were more suitable for S2 patients were predominantly common chemotherapy and targeted therapy drugs, including Paclitaxel, Vinorelbine, and Gefitinib.…”

Section: Discussionmentioning

confidence: 99%

Transcriptomics based multi-dimensional characterization and drug screen in esophageal squamous cell carcinoma

Chen

et al. 2021

EBioMedicine

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Background Esophageal squamous cell carcinoma (ESCC) remains one of the deadly cancer types. Comprehensively dissecting the molecular characterization and the heterogeneity of ESCC paves the way for developing more promising therapeutics. Methods Expression profiles of multiple ESCC datasets were integrated. ATAC-seq and RNA-seq were combined to reveal the chromatin accessibility features. A prognosis-related subtype classifier (PrSC) was constructed, and its association with the tumor microenvironment (TME) and immunotherapy was assessed. The key gene signature was validated in clinical samples. Based on the TME heterogeneity of ESCC patients, potential subtype-specific therapeutic agents were screened. Findings The common differentially expressed genes (cDEGs) in ESCC were identified. Up-regulated genes (HEATR1, TIMELESS, DTL, GINS1, RUVBL1, and ECT2) were found highly important in ESCC cell survival. The expression alterations of PRIM2, HPGD, NELL2, and TFAP2B were associated with chromatin accessibility changes. PrSC was a robust scoring tool that was not only associated with the prognosis of ESCC patients, but also could reflect the TME heterogeneity. TNS1 high fibroblasts were associated with immune exclusion. TG-101348 and Vinorelbine were identified as potential subtype-specific therapeutic agents. Besides, the application of PrSC into two immunotherapy cohorts indicated its potential value in assessing treatment response to immunotherapy. Interpretation Our study depicted the multi-dimensional characterization of ESCC, established a robust scoring tool for the prognosis assessment, highlighted the role of TNS1 high fibroblasts in TME, and identified potential drugs for clinical use. Funding A full list of funding bodies that contributed to this study can be found in the Acknowledgements section.

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“…Similarly, AZD4547, a pan-FGFR inhibitor, exhibited promising results in the National Cancer InstituteeMolecular Analysis for Therapy Choice trial (EAY131) subprotocol W, suggesting efficacy in breast (33.3%), urothelial (12.5%), and cervical (10.4%) cancers with FGFR activating mutations and fusions (Chae et al, 2020). Furthermore, evidence exists for the inhibitory role of AZD4547 in pediatric solid tumors, breast cancer, nonsmall cell lung cancer, endometritis, and head and neck cancer (Phanhthilath et al, 2020). The FGFRs are involved in the regulation of normal skin development and have also been implicated as having either a causative or suppressive role in skin cancer (Czyz, 2019).…”

Section: Effect Of Topical Azd4547 Treatment On Uvb Skin Carcinogenesismentioning

confidence: 99%

Inhibition of Fibroblast Growth Factor Receptor Attenuates UVB-Induced Skin Carcinogenesis

Thakur¹,

Khandelwal²,

Gu³

et al. 2022

Journal of Investigative Dermatology

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Mechanisms of Efficacy of the FGFR1–3 Inhibitor AZD4547 in Pediatric Solid Tumor Models

Cited by 8 publications

References 72 publications

FGFR1 is a Potential Therapeutic Target in Neuroblastoma

FGFR1 is a Potential Therapeutic Target in Neuroblastoma

Transcriptomics based multi-dimensional characterization and drug screen in esophageal squamous cell carcinoma

Inhibition of Fibroblast Growth Factor Receptor Attenuates UVB-Induced Skin Carcinogenesis

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