Gene expression profile of RAS/RAF–wild-type colorectal cancer patient-derived spheroids II
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE205787 | GEO | 2022/08/31
REPOSITORIES: GEO
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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
Project description:Genomic alterations that activate Fibroblast Growth Factor Receptor 2 (FGFR2) are common in intrahepatic cholangiocarcinoma (ICC), a deadly bile duct malignancy. FGFR kinase inhibitors (FGFRi) have shown promising efficacy against FGFR2+ ICC in clinical trials, leading to the regulatory approval of the ATP-competitive FGFR inhibitors, pemigatinib and infigratinib (BGJ398), for this subset of patients who failed standard treatment . However, the objective response rate (ORR) for each FGFR inhibitor (FGFRi) studied to date in FGFR2+ ICC is <45% and disease progression invariably arises within ~6-12 months. By employing high-throughput drug screens and signaling studies, we identified signaling feedback via the EGFR pathway as a major mediator of adaptive resistance to FGFR kinase inhibition in a set of patient-derived ICC models. To further gain insights into the synergistic effects of the EGFR/FGFR combination and address the mechanisms underlying the survival pathway reactivation, we performed RNA sequencing in our FGFR-driven ICC models (ICC21 and ICC10-6). For these studies, we treated FGFR2 fusion+ ICC cell lines ICC21/ICC10-6 with four conditions (DMSO/Infigratinib/Afatinib/Combo) for 4 hours followed by RNA sequencing.
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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:Despite initial and often dramatic responses of epidermal growth factor receptor (EGFR)-addicted lung tumors to the EGFR-specific tyrosine kinase inhibitors (TKIs), gefitinib and erlotinib, nearly all develop resistance and relapse. To explore novel mechanisms mediating acquired resistance, we employed non-small-cell lung cancer (NSCLC) cell lines bearing activating mutations in EGFR and rendered them resistant to EGFR-specific TKIs through chronic adaptation in tissue culture. In addition to previously observed resistance mechanisms including EGFR-T790M 'gate-keeper' mutations and MET amplification, a subset of the seven chronically adapted NSCLC cell lines including HCC4006, HCC2279 and H1650 cells exhibited marked induction of fibroblast growth factor (FGF) 2 and FGF receptor 1 (FGFR1) mRNA and protein. Also, adaptation to EGFR-specific TKIs was accompanied by an epithelial to mesenchymal transition (EMT) as assessed by changes in CDH1, VIM, ZEB1 and ZEB2 expression and altered growth properties in Matrigel. In adapted cell lines exhibiting increased FGF2 and FGFR1 expression, measures of growth and signaling, but not EMT, were blocked by FGFR-specific TKIs, an FGF-ligand trap and FGFR1 silencing with RNAi. In parental HCC4006 cells, cell growth was strongly inhibited by gefitinib, although drug-resistant clones progress within 10 days. Combined treatment with gefitinib and AZD4547, an FGFR-specific TKI, prevented the outgrowth of drug-resistant clones. Thus, induction of FGF2 and FGFR1 following chronic adaptation to EGFR-specific TKIs provides a novel autocrine receptor tyrosine kinase-driven bypass pathway in a subset of lung cancer cell lines that are initially sensitive to EGFR-specific TKIs. The findings support FGFR-specific TKIs as potentially valuable additions to existing targeted therapeutic strategies with EGFR-specific TKIs to prevent or delay acquired resistance in EGFR-driven NSCLC. Examination of mRNA levels in DMSO and gefitinib-resistant cultures of HCC4006 and HCC827. Each group has two replicates.
2016-03-29 | E-GEOD-79688 | biostudies-arrayexpress
Project description:Metastatic BRAFV600E colorectal cancer (CRC) confers poor prognosis and run into a bottleneck in the current treatment strategies. To identify regulatory pathways independent of the MAPK pathway in BRAFV600E CRC, we performed CRISPR-Cas9 screening, and and find targeting glutathione peroxidase 4 (GPX4) remarkably overcome BRAF inhibitor (BRAFi) ± epidermal growth factor receptor (EGFR) inhibitor (EGFRi) resistance in BRAFV600E CRC. Specifically, BRAFi ± EGFRi induced GPX4 upregulated expression and antagonized ferroptosis. Moreover, polo-like kinase 1 (PLK1) substrate activation promoted PLK1 translocation to the nucleus, activating chromobox protein homolog 8 (CBX8) phosphorylation at Ser265, which induce GPX4 expression. Targeting PLK1 promoted BRAFi ± EGFRi inhibition and triggered ferroptosis in vitro, vivo, organoid, and patient-derived xenograft model. Collectively, we demonstrate a novel PLK1–CBX8–GPX4 signaling axis relaying the ferroptosis mechanism of therapeutic resistance operated independent of MAPK signaling and suggest a clinically actionable strategy to overcome BRAFi ± EGFRi resistance in BRAFV600E CRC.
2025-02-28 | PXD058218 | Pride
Project description:With their ability to self-renew and simultaneously fuel the bulk tumor mass with highly proliferative tumor cells, cancer stem cells (CSC) are supposedly driving cancer progression. However, the CSC-phenotype in colorectal cancer (CRC) is unstable and dependent on environmental cues. Since FGF2 is essential for adult and embryonic stem cell culture to maintain self-renewal, we investigated its role in advanced CRC using tumor-derived organoids as experimental model. We found that FGF-Receptor (FGFR) inhibition prevents organoid formation in very early expanding cells but induces cyst formation when applied to already established organoids. Comprehensive transcriptome analyses revealed that the induction of the transcription factor activator protein-1 (AP-1) together with a MAPK stimulation was most prominent after FGFR-inhibition. These effects resemble mechanisms of an acquired resistance against other described tyrosine kinase inhibitors such as targeted therapies against the EGF-Receptor. Furthermore, we detected elevated expression levels of several self-renewal and stemness-associated genes in organoid cultures with active FGF2 signaling. The combined data assumes that CSC are a heterogeneous subpopulation while self-renewal is a common feature regulated by many different pathways. Finally, we highlight the effects of FGF2 signaling as one of numerous aspects of the complex regulation of stemness in cancer.
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2020-06-30 | GSE153509 | GEO
Project description:Despite initial and often dramatic responses of epidermal growth factor receptor (EGFR)-addicted lung tumors to the EGFR-specific tyrosine kinase inhibitors (TKIs), gefitinib and erlotinib, nearly all develop resistance and relapse. To explore novel mechanisms mediating acquired resistance, we employed non-small-cell lung cancer (NSCLC) cell lines bearing activating mutations in EGFR and rendered them resistant to EGFR-specific TKIs through chronic adaptation in tissue culture. In addition to previously observed resistance mechanisms including EGFR-T790M 'gate-keeper' mutations and MET amplification, a subset of the seven chronically adapted NSCLC cell lines including HCC4006, HCC2279 and H1650 cells exhibited marked induction of fibroblast growth factor (FGF) 2 and FGF receptor 1 (FGFR1) mRNA and protein. Also, adaptation to EGFR-specific TKIs was accompanied by an epithelial to mesenchymal transition (EMT) as assessed by changes in CDH1, VIM, ZEB1 and ZEB2 expression and altered growth properties in Matrigel. In adapted cell lines exhibiting increased FGF2 and FGFR1 expression, measures of growth and signaling, but not EMT, were blocked by FGFR-specific TKIs, an FGF-ligand trap and FGFR1 silencing with RNAi. In parental HCC4006 cells, cell growth was strongly inhibited by gefitinib, although drug-resistant clones progress within 10 days. Combined treatment with gefitinib and AZD4547, an FGFR-specific TKI, prevented the outgrowth of drug-resistant clones. Thus, induction of FGF2 and FGFR1 following chronic adaptation to EGFR-specific TKIs provides a novel autocrine receptor tyrosine kinase-driven bypass pathway in a subset of lung cancer cell lines that are initially sensitive to EGFR-specific TKIs. The findings support FGFR-specific TKIs as potentially valuable additions to existing targeted therapeutic strategies with EGFR-specific TKIs to prevent or delay acquired resistance in EGFR-driven NSCLC.
2016-03-29 | GSE79688 | GEO
Project description:We have shown that in PNT1a cells expressing exogenous FGFR4 Arg388 or Gly388 under the control of the EF1 promoter almost all FGFR signaling can be attributed to the transfected receptor, and the two FGFR-4 isoforms are expressed at equivalent levels in the two cell lines. Furthermore, we have shown that serum contains abundant FGFs capable of activating FGFR-4 so these initial experiments were carried out in serum to mimic physiological conditions. In such conditions the Arg388 expressing PNT1a cells display increased invasiveness and motility compared to Gly388 expressing cells. FGFR-4 Arg388 allele shows increased receptor stability and sustained receptor activation following ligand binding when compared to the Gly388 allele. However, the impact of this sustained signaling on cellular signal transduction pathways is unknown. We therefore analyzed the effect of FGFR-4 Arg388 expression on signal transduction in prostatic epithelial cells. We have found that expression of the FGFR-4 Arg388 allele leads to increased activity of the MAPK pathway, increased activity of serum response factor and AP1 and transcription of multiple genes which are correlated with aggressive clinical behavior in prostate cancer. Keywords: two group comparison To further understand the underlying molecular mechanisms of increased cell motility and invasiveness in Arg388 expressing cells, microarray studies of biological duplicates were performed on FGFR4 Arg388 and Gly388 expressing PNT1a cells using Agilent 44k whole genome expression microarrays to identify the effector genes that may be responsible for phenotypic differences between the two variants.
2011-07-01 | E-GEOD-20906 | biostudies-arrayexpress
Project description:Using liver metastases from 4 colorectal cancer patients (CRC-LM), we explored one receptor: EGFR whose signaling triggers cell proliferation and is exacerbated in many tumors.
2023-06-14 | GSE217414 | GEO