FGF/FGFR signaling in health and disease

Signal Transduction and Targeted Therapy, Journal Year: 2020, Volume and Issue: 5(1)

Published: Sept. 2, 2020

Growing evidences suggest that the fibroblast growth factor/FGF receptor (FGF/FGFR) signaling has crucial roles in a multitude of processes during embryonic development and adult homeostasis by regulating cellular lineage commitment, differentiation, proliferation, apoptosis various types cells. In this review, we provide comprehensive overview current understanding FGF its organ development, injury repair, pathophysiology spectrum diseases, which is consequence dysregulation, including cancers chronic kidney disease (CKD). context, agonists antagonists for FGF-FGFRs might have therapeutic benefits multiple systems.

Language: Английский

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The MAPK and AMPK signalings: interplay and implication in targeted cancer therapy

Journal of Hematology & Oncology, Journal Year: 2020, Volume and Issue: 13(1)

Published: Aug. 17, 2020

Abstract Cancer is characterized as a complex disease caused by coordinated alterations of multiple signaling pathways. The Ras/RAF/MEK/ERK (MAPK) one the best-defined pathways in cancer biology, and its hyperactivation responsible for over 40% human cases. To drive carcinogenesis, this promotes cellular overgrowth turning on proliferative genes, simultaneously enables cells to overcome metabolic stress inhibiting AMPK signaling, key singular node metabolism. Recent studies have shown that can also reversibly regulate hyperactive MAPK phosphorylating components, RAF/KSR family kinases, which affects not only carcinogenesis but outcomes targeted therapies against signaling. In review, we will summarize current proceedings how MAPK-AMPK signalings interplay with each other well implications clinic treatment inhibition modulators, discuss exploitation combinatory targeting both novel therapeutic intervention.

Language: Английский

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Targeting the HIF2–VEGF axis in renal cell carcinoma

Nature Medicine, Journal Year: 2020, Volume and Issue: 26(10), P. 1519 - 1530

Published: Oct. 1, 2020

Language: Английский

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Advancements in clinical aspects of targeted therapy and immunotherapy in breast cancer

Molecular Cancer, Journal Year: 2023, Volume and Issue: 22(1)

Published: July 6, 2023

Abstract Breast cancer is the second leading cause of death for women worldwide. The heterogeneity this disease presents a big challenge in its therapeutic management. However, recent advances molecular biology and immunology enable to develop highly targeted therapies many forms breast cancer. primary objective therapy inhibit specific target/molecule that supports tumor progression. Ak strain transforming, cyclin-dependent kinases, poly (ADP-ribose) polymerase, different growth factors have emerged as potential targets subtypes. Many drugs are currently undergoing clinical trials, some already received FDA approval monotherapy or combination with other treatment yet achieve promise against triple-negative (TNBC). In aspect, immune has come up promising approach specifically TNBC patients. Different immunotherapeutic modalities including immune-checkpoint blockade, vaccination, adoptive cell transfer been extensively studied setting cancer, especially approved blockers chemotherapeutic treat several trials ongoing. This review provides an overview developments advancements immunotherapies treatment. successes, challenges, prospects were critically discussed portray their profound prospects.

Language: Английский

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Fibroblast growth factor receptors in cancer: genetic alterations, diagnostics, therapeutic targets and mechanisms of resistance

British Journal of Cancer, Journal Year: 2020, Volume and Issue: 124(5), P. 880 - 892

Published: Dec. 3, 2020

Abstract Fibroblast growth factor receptors (FGFRs) are aberrantly activated through single-nucleotide variants, gene fusions and copy number amplifications in 5–10% of all human cancers, although this frequency increases to 10–30% urothelial carcinoma intrahepatic cholangiocarcinoma. We begin review by highlighting the diversity FGFR genomic alterations identified cancers current challenges associated with development clinical-grade molecular diagnostic tests accurately detect these tissue blood patients. The past decade has seen significant advancements FGFR-targeted therapies, which include selective, non-selective covalent small-molecule inhibitors, as well monoclonal antibodies against receptors. describe expanding landscape anti-FGFR therapies that being assessed early phase randomised controlled clinical trials, such erdafitinib pemigatinib, approved Food Drug Administration for treatment FGFR3 -mutated FGFR2 -fusion cholangiocarcinoma, respectively. However, despite initial sensitivity inhibition, acquired drug resistance leading cancer progression develops most This phenomenon underscores need clearly delineate tumour-intrinsic tumour-extrinsic mechanisms facilitate second-generation inhibitors novel strategies beyond on targeted therapy.

Language: Английский

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Futibatinib, an Irreversible FGFR1–4 Inhibitor, in Patients with Advanced Solid Tumors HarboringFGF/FGFRAberrations: A Phase I Dose-Expansion Study

Cancer Discovery, Journal Year: 2021, Volume and Issue: 12(2), P. 402 - 415

Published: Sept. 22, 2021

Futibatinib, a highly selective, irreversible FGFR1-4 inhibitor, was evaluated in large multihistology phase I dose-expansion trial that enrolled 197 patients with advanced solid tumors. Futibatinib demonstrated an objective response rate (ORR) of 13.7%, responses broad spectrum tumors (cholangiocarcinoma and gastric, urothelial, central nervous system, head neck, breast cancer) bearing both known previously uncharacterized FGFR1-3 aberrations. The greatest activity observed FGFR2 fusion/rearrangement-positive intrahepatic cholangiocarcinoma (ORR, 25.4%). Some acquired resistance to prior FGFR inhibitor also experienced futibatinib. manageable safety profile. most common treatment-emergent adverse events were hyperphosphatemia (81.2%), diarrhea (33.5%), nausea (30.4%). These results formed the basis for ongoing futibatinib II/III trials demonstrate potential genomically selected early-phase help identify molecular subsets likely benefit from targeted therapy. SIGNIFICANCE: This clinical tolerability across FGFR-aberrant rationale cholangiocarcinoma, cancer, gastroesophageal disease-agnostic population.This article is highlighted In Issue feature, p. 275.

Language: Английский

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PROTACs: great opportunities for academia and industry (an update from 2020 to 2021)

Signal Transduction and Targeted Therapy, Journal Year: 2022, Volume and Issue: 7(1)

Published: June 9, 2022

Abstract PROteolysis TArgeting Chimeras (PROTACs) technology is a new protein-degradation strategy that has emerged in recent years. It uses bifunctional small molecules to induce the ubiquitination and degradation of target proteins through ubiquitin–proteasome system. PROTACs can not only be used as potential clinical treatments for diseases such cancer, immune disorders, viral infections, neurodegenerative diseases, but also provide unique chemical knockdown tools biological research catalytic, reversible, rapid manner. In 2019, our group published review article “PROTACs: great opportunities academia industry” journal, summarizing representative compounds reported before end 2019. past 2 years, entire field protein experienced development, including large increase number papers on small-molecule degraders have entered will enter stage. addition PROTAC molecular glue technology, other technologies are developing rapidly. this article, we mainly summarize related targets 2020–2021 present researchers exciting developments degradation. The problems need solved briefly introduced.

Language: Английский

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Precision medicine for human cancers with Notch signaling dysregulation (Review)

International Journal of Molecular Medicine, Journal Year: 2019, Volume and Issue: unknown

Published: Dec. 4, 2019

NOTCH1, NOTCH2, NOTCH3 and NOTCH4 are transmembrane receptors that transduce juxtacrine signals of the delta‑like canonical Notch ligand (DLL)1, DLL3, DLL4, jagged (JAG)1 JAG2. Canonical signaling activates transcription BMI1 proto‑oncogene polycomb ring finger, cyclin D1, CD44, dependent kinase inhibitor 1A, hes family bHLH factor 1, related with YRPW motif MYC, NOTCH3, RE1 silencing 7 in a cellular context‑dependent manner, while non‑canonical NF‑κB Rac small GTPase 1. is aberrantly activated breast cancer, non‑small‑cell lung cancer hematological malignancies, such as T‑cell acute lymphoblastic leukemia diffuse large B‑cell lymphoma. However, inactivated small‑cell squamous cell carcinomas. Loss‑of‑function NOTCH1 mutations early events during esophageal tumorigenesis, whereas gain‑of‑function late leukemogenesis lymphomagenesis. cascades crosstalk fibroblast growth WNT tumor microenvironment to maintain stem cells remodel microenvironment. The network exerts oncogenic tumor‑suppressive effects stage‑ or (sub)type‑dependent manner. Small‑molecule γ‑secretase inhibitors (AL101, MRK‑560, nirogacestat others) antibody‑based biologics targeting ligands [ABT‑165, AMG 119, rovalpituzumab tesirine (Rova‑T) others] have been developed investigational drugs. DLL3‑targeting antibody‑drug conjugate (ADC) Rova‑T, chimeric antigen receptor‑modified T (CAR‑Ts), promising anti‑cancer therapeutics, other ADCs CAR‑Ts necrosis receptor superfamily member 17, CD19, CD22, CD30, CD79B, CD205, Claudin 18.2, (FGFR)2, FGFR3, receptor‑type tyrosine‑protein FLT3, HER2, hepatocyte receptor, NECTIN4, inactive 7, ROR1 tumor‑associated calcium signal transducer 2. could alter therapeutic framework for refractory cancers, especially diffuse‑type gastric ovarian pancreatic peritoneal dissemination. Phase III clinical trials Rova‑T patients phase trial desmoid tumors ongoing. Integration human intelligence, cognitive computing explainable artificial intelligence necessary construct Notch‑related knowledge‑base optimize Notch‑targeted therapy cancer.

Language: Английский

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Bemarituzumab in patients with FGFR2b-selected gastric or gastro-oesophageal junction adenocarcinoma (FIGHT): a randomised, double-blind, placebo-controlled, phase 2 study

The Lancet Oncology, Journal Year: 2022, Volume and Issue: 23(11), P. 1430 - 1440

Published: Oct. 14, 2022

Language: Английский

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The Role of Fibroblast Growth Factor (FGF) Signaling in Tissue Repair and Regeneration

Cells, Journal Year: 2021, Volume and Issue: 10(11), P. 3242 - 3242

Published: Nov. 19, 2021

Fibroblast growth factors (FGFs) are a large family of secretory molecules that act through tyrosine kinase receptors known as FGF receptors. They play crucial roles in wide variety cellular functions, including cell proliferation, survival, metabolism, morphogenesis, and differentiation, well tissue repair regeneration. The signaling pathways regulated by FGFs include RAS/mitogen-activated protein (MAPK), phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)–protein B (AKT), phospholipase C gamma (PLCγ), signal transducer activator transcription (STAT). To date, 22 have been discovered, involved different functions the body. Several directly or indirectly interfere with during regeneration, addition to their critical maintenance pluripotency dedifferentiation stem cells. In this review, we summarize diverse processes shed light on importance mechanisms

Language: Английский

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