Targeting COPA to enhance erdafitinib sensitivity in FGFR-altered bladder cancer
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE278672 | GEO | 2025/05/22
REPOSITORIES: GEO
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Project description:Mutations of the fibroblast growth factor receptor (FGFR) family members are frequently observed in metastatic bladder cancer. The development of erdafitinib, a pan-FGFR inhibitor, provides a significant therapeutic advance in bladder cancer, but resistance still limits its efficacy. In this study, we perform an unbiased whole-genome CRISPR-Cas9 synthetic lethal screen on FGFR-mutant bladder cancer cell lines treated with erdafitinib-targeted therapy and identify SRM as a critical contributor to erdafitinib resistance. In polyamine metabolism, SRM catalyzes the production of spermidine, which subsequently promotes the hypusination of eukaryotic translation factor 5A (eIF5A). Moreover, we demonstrate that hypusinated eIF5A (eIF5AHyp) facilitates the efficient translation of HMGA2, which in turn promotes EGFR expression. Notably, pharmacologic inhibition of SRM using MCHA enhances the efficacy of erdafitinib both in vitro and in vivo. Together, these results offer evidence of the synthetic lethality between SRM inhibition and erdafitinib, suggesting that combination treatment is a promising therapeutic strategy to overcome erdafitinib resistance for FGFR-mutant bladder cancer.
2024-12-31 | GSE276232 | GEO
Project description:Mutations of the fibroblast growth factor receptor (FGFR) family members are frequently observed in metastatic bladder cancer. The development of erdafitinib, a pan-FGFR inhibitor, provides a significant therapeutic advance in bladder cancer, but resistance still limits its efficacy. In this study, we perform an unbiased whole-genome CRISPR-Cas9 synthetic lethal screen on FGFR-mutant bladder cancer cell lines treated with erdafitinib-targeted therapy and identify SRM as a critical contributor to erdafitinib resistance. In polyamine metabolism, SRM catalyzes the production of spermidine, which subsequently promotes the hypusination of eukaryotic translation factor 5A (eIF5A). Moreover, we demonstrate that hypusinated eIF5A (eIF5AHyp) facilitates the efficient translation of HMGA2, which in turn promotes EGFR expression. Notably, pharmacologic inhibition of SRM using MCHA enhances the efficacy of erdafitinib both in vitro and in vivo. Together, these results offer evidence of the synthetic lethality between SRM inhibition and erdafitinib, suggesting that combination treatment is a promising therapeutic strategy to overcome erdafitinib resistance for FGFR-mutant bladder cancer.
2024-12-31 | GSE276411 | GEO
Project description:Targeting COPA to enhance erdafitinib sensitivity in FGFR-altered bladder cancer
| PRJNA1168176 | ENA
Project description:Background: Up to 40% of patients with estrogen receptor positive (ER+) breast cancer experience treatment resistance and disease recurrence, often caused by the upregulation of growth factor receptors. Understanding the mechanisms of resistance, and the identification of novel therapeutic targets is, therefore, of vital importance if breast cancer prognosis is to be further improved. Fibroblast growth factor receptor 1 (FGFR1) is a potential driver of endocrine resistance; however, clinically successful attempts at targeting FGFR1 activity in breast cancer are rare and may result from an inability to correctly identify patients that could benefit from such treatment. The identification of additional genes associated with an FGFR1-mediated mechanism of resistance will provide a more precise classification scheme for FGFR1-dependency in breast cancer. Methods: Live cell imaging and RNA sequencing of ER+ breast cancer cell lines (CAMA1, T47D, tamoxifen resistant T47D) were used to investigate FGFR1-dependency in breast cancer, mechanisms of endocrine resistance and the effects of treatment with tamoxifen and erdafitinib. An FGFR1-amplified ER+ breast cancer patient-derived xenograft (PDX) model was used to assess the effects of targeting FGFR1 in vivo. Gene expression analysis of human breast cancer from The Cancer Genome Atlas (TCGA) was used for clinical validation. Results: We evaluated the effects of targeting FGFR1 in ER+/HER2- breast cancer with aberrant FGFR1 amplification and/or overexpression. We found that the FGFR tyrosine kinase inhibitor (TKI) erdafitinib inhibited cell proliferation of FGFR1-amplified CAMA1 cells in vitro. Additionally, erdafitinib significantly enhanced the anti-proliferative effect of 4-hydroxytamoxifen (4-OHT) and its anti-tumor effect was also demonstrated in vivo. Further, we demonstrated that the proliferation of FGFR1-overexpressing tamoxifen-resistant T47D (TR-T47D) cells is dependent on FGFR1 activity. Moreover, these TR-T47D cells are re-sensitized to tamoxifen upon treatment with erdafitinib. Finally, we found that upregulation of genes related to epithelial-mesenchymal-transition (EMT) correlates with FGFR1 overexpression, and is reversed by FGFR inhibition. Conclusions: In this study we demonstrated that targeting FGFR1 in ER+/HER2- breast cancer with aberrant FGFR1 activity has the potential to inhibit tumor growth and to re-sensitize resistant tumors to tamoxifen. Furthermore, we identified a functional relationship between EMT, FGFR activity and endocrine resistance in breast tumorigenesis.
2022-08-01 | GSE200029 | GEO
Project description:We first verified that erdafitinib is synergistic with quisinostat in vitro and confirmed that the combinational treatment can significantly enhance the inhibition of tumor growth and prolong the survival in vivo for bladder cancers with FGFR3 fusions. Next, in order to understand the underlying molecular mechanisms of this synergy, we performed RNA-seq analysis. We revealed that quisinostat can concomitantly inhibit FGFR signaling with erdafitinib by suppressing the translation of FGFR3 fusions. In addition, quisinostat can also sensitize bladder cancer cells to erdafitinib by downregulating HDGF, which is a second mechanism of the synergy independent of FGFR signaling.
2022-10-11 | GSE214814 | GEO
Project description:Drugs that target specific gene alterations have proven beneficial in the treatment of cancer. Because cancer cells have multiple resistance mechanisms, it is important to understand the downstream pathways of the target genes and monitor the pharmacodynamic markers associated with therapeutic efficacy. We performed a transcriptome analysis to characterize the response of various cancer cell lines. We performed a transcriptome analysis to characterize the response of various cancer cell lines to a selective fibroblast growth factor receptor (FGFR) inhibitor (CH5183284/Debio 1347), a mitogen-activated protein kinase kinase (MEK) inhibitor, or a phosphoinositide 3-kinase (PI3K) inhibitor. We treated compounds for 24 hours and purified total RNA.
2016-01-06 | E-GEOD-73024 | biostudies-arrayexpress
Project description:Activation of fibroblast growth factor receptor (FGFR) signaling through mutations, amplifications, or fusions involving FGFR1, 2, 3, or 4 are seen in multiple tumors including lung, bladder, and cholangiocarcinoma. Currently, several clinical trials are evaluating the role of novel FGFR inhibitors in solid tumors. As we move forward with FGFR inhibitors clinically, we anticipate emergence of resistance with treatment. Consequently, we sought to study the mechanism(s) of acquired resistance to FGFR inhibitors using annotated cancer cell lines. We identified cancer cell lines that have activating mutations in FGFR1, 2, or 3, and treated them chronically with the selective FGFR inhibitor, BGJ398. We observed resistance to chronic BGJ398 exposure in DMS114 (small cell lung cancer, FGFR1 amplification), and RT112 (urothelial carcinoma, FGFR3 fusion/amplification) cell lines based on viability assays. Reverse phase protein array (RPPA) analysis showed increased phosphorylation of Akt (T308 and S473) and its downstream target GSK3 (S9 and S21) in both the resistant cell lines when compared to matching controls. Results of RPPA were confirmed using immunoblots. Consequently, the addition of an Akt inhibitor (GSK2141795) or siRNA was able to restore sensitivity to BGJ398 in resistant cell lines. These data suggest a role for Akt pathway in mediating acquired resistance to FGFR inhibition.
2017-08-31 | GSE92651 | GEO
Project description:Beyond acquired mutations in the estrogen receptor (ER), mechanisms of resistance to ER-directed therapies in ER+ breast cancer have not been clearly defined. We conducted a genome-scale functional screen spanning 10,135 genes to investigate genes whose overexpression confer resistance to selective estrogen receptor degraders. Pathway analysis of candidate resistance genes demonstrated that the FGFR, ERBB, insulin receptor, and MAPK pathways represented key modalities of resistance. In parallel, we performed whole exome sequencing in paired pre-treatment and post-resistance biopsies from 60 patients with ER+ metastatic breast cancer who had developed resistance to ER-targeted therapy. The FGFR pathway was altered via FGFR1, FGFR2, or FGF3/FGF4 amplifications or FGFR2 mutations in 24 (40%) of the post-resistance biopsies. In 12 of the 24 post-resistance tumors exhibiting FGFR/FGF alterations, these alterations were not detected in the corresponding pre-treatment tumors, suggesting that they were acquired or enriched under the selective pressure of ER-directed therapy. In vitro experiments in ER+ breast cancer cells confirmed that FGFR/FGF alterations led to fulvestrant resistance as well as cross-resistance to the CDK4/6 inhibitor palbociclib, through activation of the MAPK pathway. The resistance phenotypes were reversed by FGFR inhibitors and, to a lesser extent, MEK inhibitors, suggesting potential treatment strategies.
2020-06-30 | GSE153509 | GEO
Project description:<p>In this study, patients with advanced cancer across all histologies were enrolled in our IRB approved clinical sequencing program, called MI-ONCOSEQ, to go through an integrative sequencing which includes whole exome sequencing of the tumor and matched normal, and transcriptome sequencing. Four index cases were identified which harbor gene rearrangements of FGFR2 including two cholangiocarcinoma cases, a metastatic breast cancer case, and a metastatic prostate cancer case. After extending our assessment of FGFR rearrangements across multiple tumor cohorts, including TCGA, we identified FGFR gene fusions with intact kinase domains of FGFR1, FGFR2, or FGFR3 in cholangiocarcinoma, breast cancer, prostate cancer, lung squamous cell cancer, bladder cancer, thyroid cancer, oral cancer, glioblastoma, and head and neck squamous cell cancer. All FGFR fusion partners tested exhibit oligomerization capability, suggesting a shared mode of kinase activation. Overexpression of FGFR fusion proteins in vitro induced cell proliferation, and bladder cancer cell lines that harbors FGFR3 fusion proteins exhibited enhanced susceptibility to pharmacologic inhibition in vitro and in vivo. Due to the combinatorial possibilities of FGFR family fusion to a variety of oligomerization partners, clinical sequencing efforts which incorporate transcriptome analysis for gene fusions are poised to identify rare, targetable FGFR fusions across diverse cancer types.</p>
| phs000602 | dbGaP
Project description:We would like to propose a novel parameter that helps predict the chemosensitivity of cancer patients to FGFR inhibitors (FGFRi). Although FGFRi were introduced into the clinical trials on a variety of cancer types, they were found to be particularly efficacious on urothelial cancer and on cholangiocarcinoma for which the FDA had approved several compounds based on clinical studies. The enrollment criteria in such clinical trials were genomic changes in the FGFR genes including amplifications, translocations that caused gene fusions, and point mutations. By scrutinizing the published data on these reports, we have noticed an unresolved issue. Namely, most of these reports showed waterfall plots where tumors of some good fractions of enrolled patients responded well, demonstrating efficacy of the FGFRi. Importantly, however, there were sizable subsets in which tumors did not respond to the FGFRi despite that the patients’ tumors carried the genomic changes that met the enrollment criteria. As already established, both FGFR and EGFR share the downstream signaling pathway of MAPK activation as well as other pathways. Accordingly, it is conceivable that chemotherapeutic inhibition of FGFR alone may leave the MAPK signaling unaffected when the signaling through EGFR is relatively strong. To test this hypothesis, we calculated the FGFR to EGFR mRNA ratio (F/E for short) based on the RNA sequencing data from the Broad Institute Cancer Cell Line Encyclopedia (https://portals.broadinstitute.org/ccle) of cholangiocarcinoma and urothelial cancer cell lines for which FGFRi chemosensitivity had been published in preclinical studies. Because human FGFR has four paralogs FGFR1–4, we first summed up the expression levels of FGFR1–4 mRNAs by adding the read numbers per MB of FGFR paralogs (sumFGFR). To take EGFR expression into consideration, we then divided this number with that of EGFR; F/E. In six biliary tract cancer cell lines tested, two responsive cell lines had higher F/E ratios of 9.5 and 9.0, whereas four non-responsive lines had substantially lower ratios of 0.1–1.8. In 22 urothelial cancer cell lines, four of the five responsive lines showed F/E of 2.8–4.9, whereas 17 non-responsive lines had 0.01–2.7. To obtain further insights into the F/E ratio, we looked into our patient-derived colorectal cancer (CRC)-stem cell lines. Seven (28%) of 25 RAS/RAF-wild type CRC-stem cell lines responded to the pan-FGFRi erdafitinib singly in culture whereas 21 (84%) did respond to erdafitinib in combination with an EGFR inhibitor (erlotinib). The seven singly responsive cell lines showed relatively high F/E ranging 11–207 with the mean of 46, whereas the 18 non-responsive lines had the ratio of 3.5–37 with the mean at 12. These results suggest that F/E can be a useful biomarker also for colorectal cancer chemosensitivity where EGFR expression level can vary widely. Taken together, F/E is another strong predictor of responses to FGFRi that is as useful as the current genomic criteria that are based on the FGFR genomic changes.
2021-11-22 | GSE189212 | GEO