Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver and it is the third leading cause of cancer-related deaths worldwide. Recently, aberrant signaling through the FGF19/FGFR4 axis has been implicated in HCC. Here, we describe the development of FGF401, a highly potent and selective, first in class, reversible-covalent small-molecule inhibitor of the kinase activity of FGFR4. FGF401 is exquisitely selective for FGFR4 versus the other FGFR paralogues FGFR1, FGFR2, FGFR3, and all other kinases in the kinome. FGF401 has excellent drug-like properties showing a robust pharmacokinetic/pharmacodynamics/efficacy relationship, driven by a fraction of time above the phospho-FGFR4 IC₉₀ value. FGF401 has remarkable antitumor activity in mice bearing HCC tumor xenografts and patient-derived xenograft models that are positive for FGF19, FGFR4, and KLB. FGF401 is the first FGFR4 inhibitor to enter clinical trials, and a phase I/II study is currently ongoing in HCC and other solid malignancies.
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PMID:FGF401, A First-In-Class Highly Selective and Potent FGFR4 Inhibitor for the Treatment of FGF19-Driven Hepatocellular Cancer. 3140 33

Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality worldwide with no clinically confirmed oncogenic driver. Although preclinical studies implicate the FGF19 receptor FGFR4 in hepatocarcinogenesis, the dependence of human cancer on FGFR4 has not been demonstrated. Fisogatinib (BLU-554) is a potent and selective inhibitor of FGFR4 and demonstrates clinical benefit and tumor regression in patients with HCC with aberrant FGF19 expression. Mutations were identified in the gatekeeper and hinge-1 residues in the kinase domain of FGFR4 upon disease progression in 2 patients treated with fisogatinib, which were confirmed to mediate resistance in vitro and in vivo. A gatekeeper-agnostic, pan-FGFR inhibitor decreased HCC xenograft growth in the presence of these mutations, demonstrating continued FGF19-FGFR4 pathway dependence. These results validate FGFR4 as an oncogenic driver and warrant further therapeutic targeting of this kinase in the clinic. SIGNIFICANCE: Our study is the first to demonstrate on-target FGFR4 kinase domain mutations as a mechanism of acquired clinical resistance to targeted therapy. This further establishes FGF19-FGFR4 pathway activation as an oncogenic driver. These findings support further investigation of fisogatinib in HCC and inform the profile of potential next-generation inhibitors.See related commentary by Subbiah and Pal, p. 1646.This article is highlighted in the In This Issue feature, p. 1631.
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PMID:Acquired On-Target Clinical Resistance Validates FGFR4 as a Driver of Hepatocellular Carcinoma. 3179 21

Outcomes for patients with advanced hepatocellular carcinoma (HCC) remain poor despite recent progress in drug development. Emerging data implicate FGF19 as a potential HCC driver, suggesting its receptor, FGFR4, as a novel therapeutic target. We evaluated fisogatinib (BLU-554), a highly potent and selective oral FGFR4 inhibitor, in a phase I dose-escalation/dose-expansion study in advanced HCC using FGF19 expression measured by IHC as a biomarker for pathway activation. For dose escalation, 25 patients received 140 to 900 mg fisogatinib once daily; the maximum tolerated dose (600 mg once daily) was expanded in 81 patients. Fisogatinib was well tolerated; most adverse events were manageable, grade 1/2 gastrointestinal events, primarily diarrhea, nausea, and vomiting. Across doses, the overall response rate was 17% in FGF19-positive patients [median duration of response: 5.3 months (95% CI, 3.7-not reached)] and 0% in FGF19-negative patients. These results validate FGFR4 as a targetable driver in FGF19-positive advanced HCC. SIGNIFICANCE: Fisogatinib elicited clinical responses in patients with tumor FGF19 overexpression in advanced HCC. These results validate the oncogenic driver role of the FGFR4 pathway in HCC and the use of FGF19 as a biomarker for patient selection.See related commentary by Subbiah and Pal, p. 1646.This article is highlighted in the In This Issue feature, p. 1631.
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PMID:First-in-Human Phase I Study of Fisogatinib (BLU-554) Validates Aberrant FGF19 Signaling as a Driver Event in Hepatocellular Carcinoma. 3179 21

Liquid biopsy is an emerging technique for noninvasive detection of various cancers. Majority of liquid biopsy tests still, however, use solitary type of biomarkers with unsatisfactory sensitivity and specificity. To this end, a combined approach of circulating tumor cells (CTCs) and salivary mRNA biomarkers was evaluated for discriminating non-small-cell lung cancer (NSCLC) from healthy controls.Our study included a discovery phase to find multiple biomarkers, and an independent validation phase to confirm the applicability of the selected biomarkers. In the discovery phase, CTC level in blood and 5 mRNA biomarkers in saliva (i.e., CCNI, Epidermal growth factor receptor [EGFR], FGF19, FRS2, and GREB1) were measured for 140 NSCLC patients and 140 healthy controls, followed by developing a predictive model. Next, this panel of biomarkers was applied to another patient cohort consisted of 60 patients with NSCLC and 60 healthy controls in the validation phase.We found that our novel biomarker panel could differentiate patients with NSCLC from healthy controls with high sensitivity (92.1%) and high specificity (92.9%) in the discovery phase. In the validation phase, we achieved sensitivity of 88.3% and specificity of 90.0%.To our best knowledge, it is the first time that a combined use of CTC and salivary mRNA biomarkers were applied for noninvasive detection of NSCLC.
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PMID:Combined use of circulating tumor cells and salivary mRNA to detect non-small-cell lung cancer. 3208 83

Lung cancer occurrence and associated mortality ranks top in all countries. Despite the rapid development of targeted and immune therapies, many patients experience relapse within a few years. It is urgent to uncover the mechanisms that drive lung cancer progression and identify novel molecular targets. Our group has previously identified FGF19 as a prognostic marker and potential driver gene of lung squamous cell carcinomas (LSQ) in Chinese smoking patients. However, the underlying mechanism of how FGF19 promotes the progression of LSQ remains unclear. In this study, we characterized and confirmed that FGF19 serves as an oncogenic driver in LSQ development and progression, and reported that the amplification and high expression of FGF19 in LSQ was significantly associated with poor overall and progression-free survival. A higher serum level of FGF19 was found in lung cancer patients, which could also serve as a novel diagnostic index to screen lung cancer. Overproduction of FGF19 in LSQ cells markedly promoted cell growth, progression and metastasis, while downregulating FGF19 effectively inhibited LSQ progression in vitro and in vivo. Moreover, downregulating the receptor FGFR4 was also effective to suppress the growth and migration of LSQ cells. Since FGF19 could be induced by smoking or endoplasmic reticulum stress, to tackle the more malignant FGF19-overproducing LSQ, we reported for the first time that inhibiting mTOR pathway by using AZD2014 was effective and feasible. These findings have offered a new strategy by using anti-FGF19/FGFR4 therapy or mTOR-based therapy in FGF19-driven LSQ.
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PMID:Enhanced autocrine FGF19/FGFR4 signaling drives the progression of lung squamous cell carcinoma, which responds to mTOR inhibitor AZD2104. 3211 83

Fibroblast growth factor (FGF) receptor 4 (FGFR4) belongs to a family of tyrosine kinase receptor. FGFR4 is highly activated in certain types of cancer and its activation is closely associated with its specific ligand, FGF19. Indeed, FGF19-FGFR4 signaling is implicated in many cellular processes including cell proliferation, migration, metabolism, and differentiation. Since active FGF19-FGFR4 signaling acts as an oncogenic pathway in certain types of cancer, the development and therapeutic evaluation of FGFR4-specific inhibitors in cancer patients is a topic of significant interest. In this review, we aim to provide an updated overview of currently-available FGFR4 inhibitors and their ongoing clinical trials, as well as upcoming potential therapeutics. Further, we examined the possibility of enhancing the therapeutic efficiency of FGFR4 inhibitors in cancer patients. We also discussed the underlying molecular mechanisms of oncogenic activation of FGFR4 by FGF19.
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PMID:Dissecting the Role of the FGF19-FGFR4 Signaling Pathway in Cancer Development and Progression. 3215 50

Cholangiocarcinoma (CCA) is a primary malignancy, which is often diagnosed as locally advanced or metastatic. Previous studies have revealed genomic characteristics of CCA in Western patients, however comprehensive genomic features of CCA in Chinese patients have not been well understood. To explore the specific genomic characteristics of Chinese patients with CCA, a total of 66 patients with CCA, including 44 intrahepatic CCA (iCCA) and 22 extrahepatic CCA (exCCA) cases, were studied. The most commonly altered genes in CCAs were TP53 (62.12%, 41/66), KRAS (36.36%, 24/66), SMAD4 (24.24%, 16/66), TERT (21.21%, 14/66), ARID1A (19.70%, 13/66), CDKN2A (19.70%, 13/66), KMT2C (9.09%, 6/66) and RBM10 (9.09%, 6/66), ERBB2 (7.58%, 5/66) and BRAF (7.58%, 5/66). Many gene mutations, including STK11, CCND1 and FGF19, were only found in iCCA. RBM10 mutations were found to be significantly higher in exCCA. The gene mutations of neurofibromin 1, STK11, CCND1 and FBXW7 specifically occurred in males, whereas gene mutations of ERBB2, AXIN2 and CREBBP specifically occurred in females. ERBB2 mutations were significantly associated with the sex of patients with CCA. Mutations in PIK3CA, FGFR2 and ZNF750 were significantly associated with the age of patients with CCA and TERT mutations were significantly associated with tumor differentiation. Alterations in KMT2C, PBRM1, AXIN2, MAGI2, BRCA2 and SPTA1 were associated with tumor mutational burden. The findings of the present study suggest that targeted sequencing, using next-generation sequencing technology, provides comprehensive and accurate information on genomic alterations, which will provide novel potential biomarkers for the diagnosis of CCA and may guide precise therapeutic strategies for Chinese patients with CCA.
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PMID:Comprehensive genomic profile of cholangiocarcinomas in China. 3225 10

Breast carcinomas (BCs) are genetically heterogeneous and associated with numerous mutations which can be used to predict outcomes and initiate targeted therapies. We investigated clinicopathologic characteristics associated with gene mutations detected using the FoundationOne CDx assay in a cohort of 223 clinically advanced BCs (66 locally recurrent and 157 metastatic) from our institution. One hundred fifty unique mutations were identified (total 1008) in the cohort, with the most prevalent (>10%) including TP53 (53.8%), PIK3CA (35%), MYC (22%), CCND1 (19.7%), FGF19 (19.7%), FGF4 (16.6%), FGF3 (16.1%), ZNF703 (14.8%), ESR1 (13.9%), FGFR1 (13.5%), PTEN (12.1%), and CDH1 (10.8%). ERBB2 genetic alteration was most common in human epidermal growth factor receptor 2 (HER2)-positive BCs, and GATA3 and ESR1 mutations were only identified in hormone receptor-positive BC. Mutations enriched in triple-negative BCs (TNBCs) included TP53, PTEN, RB1, and CDKN2A/B. CDH1 mutation was predominantly found in lobular carcinomas, and PIK3CA mutation was also enriched. Mutations enriched in metaplastic carcinomas with heterologous mesenchymal differentiation included TP53, PTEN, MCL1, CDKN2A/B, and NOTCH2. An increase in mutations of CCND1, FGF19, FGF4, FGF3, ESR1, and EMSY was identified in metastatic BCs compared with locally recurrent BCs. Overall, PIK3CA was the most frequent clinically actionable genetic alteration (35%), followed by MYC (22%), CCND1 (19.7%), and FGF3/FGF4/FGFR1 (16%). In conclusion, our study provides genetic insight into the biology of advanced BCs and summarizes their most frequent clinically actionable genetic alterations, generating useful genomic information for potential improvement of patient management.
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PMID:Genetic alterations and their association with clinicopathologic characteristics in advanced breast carcinomas: focusing on clinically actionable genetic alterations. 3244 52

In hepatocellular carcinoma (HCC), a subset of cells defined by high CD44 and CD133 expression has been reported to possess cancer stem-like cell (CSC) characteristics and to be associated with a poor prognosis. Since the approval of the multi-kinase inhibitor, lenvatinib, for patients with unresectable HCC, two such inhibitors (sorafenib and lenvatinib) have been employed as first-line systemic chemotherapeutics for these patients. Based on differences in the kinase-affinity profiles between these two drugs, evidence has suggested that both exert different effects on HCC, although these differences are not fully characterized. In this study, using in vitro and a preclinical in vivo xenograft mouse model, we showed that lenvatinib alone (not sorafenib or the cytotoxic agent, 5-fluorouracil) diminished CD44High/CD133High CSCs in HCC. Furthermore, western blotting and RT-PCR analysis revealed that the expression of fibroblast growth factor receptor (FGFR)-1 to 4 differed between CD44High/CD133High CSCs and control cells. Analysis of the effects of selective FGFR inhibitors and FGFR small interfering RNAs on CSCs in HCC revealed that lenvatinib diminished CSCs in HCC by inhibiting FGFR1-3 signaling, however, FGFR4 signaling was not impacted. Finally, we showed that FGF2 and FGF19 were involved in maintaining CD44High/CD133High CSCs in HCC, potentially, via FGFR1-3. The findings provide novel mechanistic insights into the effects of lenvatinib on CSCs in HCC and provide clues for developing effective targeted therapies against CSCs in HCC.
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PMID:Lenvatinib suppresses cancer stem-like cells in HCC by inhibiting FGFR 1-3 signaling, but not FGFR4 signaling. 3244 10

Background: Breast cancer (BC) is a type of disease with high heterogeneity. Molecular profiling, by revealing the intrinsic nature of its various subtypes, has extensively improved the therapeutic management of BC patients. However, the genomic mutation landscape of Chinese metastatic BC has not been fully explored. Methods: Matched plasma and mononuclear cells from 290 Chinese women with metastatic BC were sequenced using either of the two commercially-available panels consisting of 520 cancer-related and 108 BC-related genes. Both panels cover the same critical regions of 91 genes. The circulating tumor DNA mutation profile from our cohort was then compared with publicly-available metastatic BC datasets from Memorial Sloan Kettering Cancer Center (MSKCC) and Pan-cancer analysis of whole genomes (PCAWG). Results: A total of 1,201 mutations spanning 91 genes were detected from 234 patients, resulting in a mutation detection rate of 80.7%. TP53 (64.1%) was the gene with highest mutation frequency, followed by PIK3CA (31%), PTEN (11%), and RB1 (10%). Copy number amplifications (CNAs) in MYC (14.1%), FGFR1 (13.3%), CCND1 (6.6%), FGF3 (6.6%), FGF4 (6.2%) and FGF19 (6.2%) were also detected from our cohort. TP53 mutations were significantly more frequent among triple negative BC (TNBC), HR-/HER2+, and HR+/HER2+ BC, while less common in HR+/HER2- (P < 0.01). Meanwhile, PIK3CA mutations were significantly more frequent among HR+/HER2+, HR+/HER2-, and HR-/HER2+ BC, while less common in TNBC (P < 0.01). Pathogenic or likely pathogenic BRCA1/2 germline mutations were detected in 5.9% of the cohort and 4.4% in TNBC subgroup. Maximum allelic fraction (maxAF) of TP53, RB1, and PIK3CA mutations were associated with multiple organ metastasis. Patients with PIK3CA, PTEN, and RB1 mutation were more likely to have liver metastasis (P < 0.02). Compared with MSKCC and PCAWG dataset, Chinese patients had observably difference in genetic variation rates in different molecular subtypes (TNBC: TP53 73.0 vs. 91.5%, P < 0.001; PIK3CA 21.2 vs. 13.2%, P = 0.061; HR+/HER2-: FGFR1 3.3 vs. 0.7%, P = 0.035; TP 53 46.2 vs. 27.7%, P < 0.001; RB1 6.6 vs. 2.7%, P = 0.046; CDKN2A 7.7 vs. 1.0%, P < 0.001; PIK3CA 30.8 vs. 44.2%, P = 0.012; CDH1 1.1 vs. 18.2%, P < 0.001; GATA3 7.7 vs. 17.2%, P = 0.02). Conclusions: A distinct gene mutation profile was elucidated in Chinese women with metastatic BC, justifying further research. Liquid biopsy provides a quick, real-time, and minimally invasive tool for future clinical trial and routine practice.
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PMID:Characterizations of Cancer Gene Mutations in Chinese Metastatic Breast Cancer Patients. 3269 76


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