Article
Genetics & Heredity
Ruirui Zhang, Huanyu Zhao, Hongmei Yuan, Jian Wu, Haiyan Liu, Suan Sun, Zhengwei Zhang, Jiayang Wang
Summary: This study reveals that circARVCF enhances DDP resistance in GC by elevating FGFR1 through sponging miR-1205.
FRONTIERS IN GENETICS
(2021)
Article
Biochemistry & Molecular Biology
Jin-Ah Kim, Noah E. Berlow, Melvin Lathara, Narendra Bharathy, Leah R. Martin, Reshma Purohit, Megan M. Cleary, Qianqian Liu, Joel E. Michalek, Ganapati Srinivasa, Bonnie L. Cole, Sonja D. Chen, Charles Keller
Summary: In this study, the role of nuclear FGFR1 (nFGFR1) in radiation resistance of osteosarcoma was investigated. The activation of nFGFR1 was found to contribute to cell survival and radiation resistance in osteosarcoma cells. Furthermore, inhibition of nFGFR1 was shown to reverse radiation resistance. Thus, nFGFR1 could potentially serve as a therapeutic target or a biomarker for radiation therapy in osteosarcoma.
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
(2022)
Article
Oncology
Monica Sanchez-Guixe, Cinta Hierro, Jose Jimenez, Cristina Viaplana, Guillermo Villacampa, Erika Monelli, Fara Braso-Maristany, Zighereda Ogbah, Mireia Pares, Marta Guzman, Judit Grueso, Olga Rodriguez, Mafalda Oliveira, Analia Azaro, Elena Garralda, Josep Tabernero, Oriol Casanovas, Maurizio Scaltriti, Aleix Prat, Rodrigo Dienstmann, Paolo Nuciforo, Cristina Saura, Mariona Graupera, Ana Vivancos, Jordi Rodon, Violeta Serra
Summary: FGFR1 amplification is common in breast cancer and is associated with resistance to endocrine therapy and CDK4/6 inhibitors. High levels of FGFR1-4 mRNA expression are predictive of response to FGFRis, while MTKIs show higher response rates. These findings suggest that tailored therapy based on high mRNA levels may be effective in treating breast cancer patients.
CLINICAL CANCER RESEARCH
(2022)
Article
Oncology
Alberto Servetto, Rahul Kollipara, Luigi Formisano, Chang-Ching Lin, Kyung-Min Lee, Dhivya R. Sudhan, Paula I. Gonzalez-Ericsson, Sumanta Chatterjee, Angel Guerrero-Zotano, Saurabh Mendiratta, Hiroaki Akamatsu, Nicholas James, Roberto Bianco, Ariella B. Hanker, Ralf Kittler, Carlos L. Arteaga
Summary: FGFR1 overexpression in the nucleus of breast cancer cells is associated with endocrine resistance in ER+ breast cancer. Nuclear FGFR1 influences gene transcription and promotes resistance to estrogen suppression and fulvestrant. Treatment with FGFR tyrosine kinase inhibitors does not affect nuclear FGFR1 activity, supporting the development of strategies to inhibit nuclear FGFR1 in ER+/FGFR1 overexpressing breast cancer.
CLINICAL CANCER RESEARCH
(2021)
Article
Oncology
Yang Chen, Jingya Han, Yan Zhao, Xinming Zhao, Mengmeng Zhao, Jingmian Zhang, Jianfang Wang
Summary: This study proposes an imaging method for assessing FGFR1 expression, utilizing [18F]F-FGFR1 as a peptide probe. In vitro and in vivo experiments demonstrate that [18F]F-FGFR1 shows high stability, affinity, specificity, and good imaging capacity in FGFR1-overexpressing tumors.
FRONTIERS IN ONCOLOGY
(2023)
Article
Genetics & Heredity
Elena I. Fomchenko, Benjamin C. Reeves, William Sullivan, Asher M. Marks, Anita Huttner, Kristopher T. Kahle, E. Zeynep Erson-Omay
Summary: Pilomyxoid astrocytomas are an aggressive subtype of astrocytoma without WHO grading, often affecting the hypothalamic/chiasmatic region. This study identified two somatic activating mutations affecting FGFR1 in the patient's tumor, suggesting they may have occurred simultaneously. The use of FGFR inhibitors in addition to other targeted therapies may be an effective strategy in treating pilomyxoid astrocytomas.
MOLECULAR GENETICS & GENOMIC MEDICINE
(2021)
Article
Biochemistry & Molecular Biology
Yujie Shi, Zhikun Ma, Qiong Cheng, Yudan Wu, Amanda B. Parris, Lingfei Kong, Xiaohe Yang
Summary: The study revealed that FGFR1 overexpression renders breast cancer cells resistant to metformin by activating IRS1 and IGF1R. Targeting IRS1 can increase sensitivity to metformin in FGFR1 overexpressing cells. IRS1 acts as a critical mediator in the crosstalk between FGFR1 and IGF1R pathways.
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH
(2021)
Article
Oncology
Mikkel G. Terp, Kirstine Jacobsen, Miguel Angel Molina, Niki Karachaliou, Hans C. Beck, Jordi Bertran-Alamillo, Ana Gimenez-Capitan, Andres F. Cardona, Rafael Rosell, Henrik J. Ditzel
Summary: Resistance to EGFR tyrosine kinase inhibitors (TKIs) in NSCLC patients is often associated with increased FGFR1 expression and Akt activation, leading to the development of targeted therapy strategies for overcoming resistance. Combination therapy targeting both FGFR and Akt has shown superior growth inhibition of resistant cells in vitro and in vivo, providing a promising rationale for future clinical trials in NSCLC patients.
NPJ PRECISION ONCOLOGY
(2021)
Article
Oncology
Koh Furugaki, Takaaki Fujimura, Hayato Mizuta, Takuya Yoshimoto, Takashi Asakawa, Yasushi Yoshimura, Shigeki Yoshiura
Summary: This study found that the anti-cancer compound FGFR1 can promote the survival of ALK-positive drug-tolerant persister (DTP) cells. The high expression of FGFR1 and FGF2 is associated with an increased risk of progression-free survival in patients with ALK fusion-positive non-small cell lung cancer. Combination therapy with FGFR and targeted TKIs can enhance cell inhibition and prevent the reactivation of compensatory ERK signaling, offering a potent treatment strategy to prevent acquired drug resistance in different types of cancers.
NPJ PRECISION ONCOLOGY
(2023)
Article
Chemistry, Multidisciplinary
Zi-jian Zhang, Qi-fang Wu, An-qi Ren, Qian Chen, Jiang-zhou Shi, Jia-peng Li, Xi-yu Liu, Zhi-jie Zhang, Yu-zhe Tang, Yuan Zhao, Ning-ning Yao, Xiao-yu Zhang, Chang-peng Liu, Ge Dong, Jia-xuan Zhao, Mei-jun Xu, Yun-qiang Yue, Jia Hu, Fan Sun, Yu Liu, Qi-lin Ao, Fu-ling Zhou, Hong Wu, Tong-cun Zhang, Hai-chuan Zhu
Summary: The study revealed that FGFR1 is significantly upregulated in human T-cell acute lymphoblastic leukemia (T-ALL) and is inversely correlated with patient prognosis. Knockdown of FGFR1 suppressed T-ALL growth and progression, but T-ALL cells were resistant to FGFR1 inhibitors. Mechanistically, FGFR1 inhibitors induced ATF4 expression through chromatin accessibility and translational activation, leading to amino acid metabolic reprogramming and mTORC1 activation, which contributed to drug resistance in T-ALL cells. Targeting FGFR1 and mTOR showed synergistic anti-leukemic efficacy.
ACTA PHARMACOLOGICA SINICA
(2023)
Article
Oncology
Jakub Szymczyk, Martyna Sochacka, Patryk Chudy, Lukasz Opalinski, Jacek Otlewski, Malgorzata Zakrzewska
Summary: This study investigated the impact of FGF1 and FGFR1 activity on tubulin-targeting drugs, revealing differences in drug sensitivity in FGFR1-positive cells. Inhibition of FGFR1 activation could increase drug effectiveness, while FGF1 activation through FGFR1 reduced apoptosis induced by the drugs. These findings suggest potential pathways for cancer cell survival and drug resistance prevention.
FRONTIERS IN ONCOLOGY
(2022)
Article
Multidisciplinary Sciences
Xiaolong Zhu, Cong Qiu, Yiran Wang, Yuanqing Jiang, Yefeng Chen, Linge Fan, Ruizhe Ren, Yunyun Wang, Yu Chen, Yanzhi Feng, Xiaofei Zhou, Yunhui Zhu, Zhen Ge, Dongwu Lai, Lingfeng Qin, Michael Simons, Luyang Yu
Summary: FGFR1 SUMOylation, regulated by SENP1, controls angiogenic signaling pathway, competing with VEGFR2 to recruit FRS2 alpha, thus switching signals in hypoxia and normoxia angiogenic environments.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Oncology
Omar Elakad, Bjoern Haeupl, Vera Labitzky, Sha Yao, Stefan Kueffer, Alexander von Hammerstein-Equord, Bernhard C. Danner, Manfred Juecker, Henning Urlaub, Tobias Lange, Philipp Stroebel, Thomas Oellerich, Hanibal Bohnenberger
Summary: This study identified a CD44/PAK1/AKT signaling axis as a common resistance mechanism to FGFR1 inhibition in lung cancer. The activation levels of CD44/PAK1/AKT could help predict response to FGFR1 inhibition, and the combination of AKT and FGFR1 inhibitors may be effective in treating patients with FGFR1-dependent lung cancer.
NPJ PRECISION ONCOLOGY
(2022)
Article
Nutrition & Dietetics
Leonard Spranger, January Weiner, Josephine Bredow, Ulrike Zeitz, Ulrike Grittner, Michael Boschmann, Sophia Dickmann, Nicole Stobaeus, Reiner Jumpertz-von Schwartzenberg, Maria Brachs, Joachim Spranger, Knut Mai
Summary: This study aims to investigate the long-term effects of weight loss and metabolism improvement on obesity, and found that the specific impact of negative energy balance or modified body composition on metabolism and weight regain is still unclear. Through a randomized controlled trial, researchers found that weight loss had effects on insulin sensitivity and lean body mass, while negative energy balance had no additional effect on insulin sensitivity. Furthermore, the adaptation of body composition and metabolism may be related to the FGFR1 signaling pathway.
CLINICAL NUTRITION
(2023)
Article
Oncology
Flora Cimmino, Annalaura Montella, Matilde Tirelli, Marianna Avitabile, Vito Alessandro Lasorsa, Feliciano Visconte, Sueva Cantalupo, Teresa Maiorino, Biagio De Angelis, Martina Morini, Aurora Castellano, Franco Locatelli, Mario Capasso, Achille Iolascon
Summary: FGFR1 is an actionable driver oncogene in neuroblastoma (NB), and targeting FGFR1 mutations may be a promising therapy for patients with therapy-resistant NB.
CANCER CELL INTERNATIONAL
(2022)
Article
Chemistry, Medicinal
Cheng Mo, Zhang Zhang, Yupeng Li, Minhao Huang, Jian Zou, Jinfeng Luo, Zheng-Chao Tu, Yong Xu, Xiaomei Ren, Ke Ding, Xiaoyun Lu
ACS MEDICINAL CHEMISTRY LETTERS
(2020)
Article
Chemistry, Medicinal
Jiaqian Xu, Zhang Zhang, Ligen Lin, Hongyan Sun, Lorenzo V. White, Ke Ding, Zhengqiu Li
ACS MEDICINAL CHEMISTRY LETTERS
(2020)
Article
Pharmacology & Pharmacy
Liang Jiang, Yuting Wang, Qian Li, Zhengchao Tu, Sihua Zhu, Sanfang Tu, Zhang Zhang, Ke Ding, Xiaoyun Lu
Summary: A new class of selective Bcr-Abl(T315I) proteolysis-targeting chimeric degraders were designed, synthesized, and evaluated, with 7o exhibiting the most potent degradation efficacy and significant tumor regression in cell and animal models.
ACTA PHARMACEUTICA SINICA B
(2021)
Editorial Material
Chemistry, Medicinal
Craig W. Lindsley, James Barrow, Kelly Chibale, Maria Laura Bolognesi, Stuart Conway, William Denny, Ke Ding, Stefan Laufer, Luhua Lai, Hong Liu, Nouri Neamati, Takayoshi Suzuki, Nicholas Meanwell, Wendy Young
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Medicinal
Xiaoyun Lu, Jeff B. Smaill, Adam Patterson, Ke Ding
Summary: Small molecule covalent kinase inhibitors (CKIs) have advantages for sustained target inhibition and high selectivity, with major medicinal chemistry strategies involving the addition of a warhead to a reversible lead/inhibitor scaffold to generate CKIs, while also facing challenges in drug discovery in this area.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Zhen Zhang, Jie Li, Hao Chen, Jing Huang, Xiaojuan Song, Zheng-Chao Tu, Zhang Zhang, Lijie Peng, Yang Zhou, Ke Ding
Summary: Aberrant FGF19/FGFR4 signaling has been identified as an oncogenic driver for human hepatocellular carcinoma (HCC). A new series of inhibitors targeting FGFR4 have been synthesized, and the representative compound 9ka showed potent activity against FGFR4 with excellent kinome selectivity. Compound 9ka also demonstrated favorable pharmacokinetic properties and induced significant tumor regression in a mouse model without apparent toxicity. Compound 9ka may serve as a promising lead compound for further development of anticancer drugs.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Jibu Lu, Yongjun Huang, Jing Huang, Rui He, Minhao Huang, Xiaoyun Lu, Yong Xu, Fengtao Zhou, Zhang Zhang, Ke Ding
Summary: The first examples of threonine tyrosine kinase (TTK) PROTACs were successfully designed and synthesized, showing strong degradation effects in human colorectal cancer cells and potential anticancer activities.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Zhen Wang, Weixue Huang, Kaijie Zhou, Xiaomei Ren, Ke Ding
Summary: Protein kinases have been proven to be effective targets for cancer drug discovery, but most drugs inhibit kinase catalytic activity by binding to ATP-site. Recent studies have shown that kinases also have noncatalytic functions, which play important roles in cellular signaling and cell fate controls. Small-molecule modulators targeting the noncatalytic functions of kinases have emerged as promising therapeutic strategies. This article summarizes the noncatalytic functions of kinases and discusses the progress in developing small-molecule modulators. It is speculated that targeting the noncatalytic functions could open a new direction for kinase-based drug discovery.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Peng Lyu, Kaili Jiang, Yuee Zhou, Jun Hu, Yu Chang, Zhang Zhang, Minhao Huang, Zhi-Min Zhang, Ke Ding, Piliang Hao, Ligen Lin, Zhengqiu Li
Summary: This study successfully identified the cellular off-target NT5DC1 of HP-1, a potential drug candidate for non-small cell lung cancer, through chemical proteomics and bioimaging studies.
ACS MEDICINAL CHEMISTRY LETTERS
(2022)
Article
Chemistry, Medicinal
Zuqin Wang, Jie Wang, Yongjin Wang, Shuang Xiang, Xiaojuan Song, Zhengchao Tu, Yang Zhou, Zhi-Min Zhang, Zhang Zhang, Ke Ding, Xiaoyun Lu
Summary: In this study, a novel TRK inhibitor 7b was reported. It is a highly selective macrocycle-based potent type II inhibitor that exhibits high inhibitory activity against TRK fusion proteins and wild type. Additionally, 7b showed potent antiproliferative activity against various mutants and displayed extraordinary selectivity for phosphorylation.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Yue Liu, Jiacong Liu, Xianfang Zhang, Cuiping Guo, Zhi-Min Zhang, Xiwen Xing, Ke Ding, Zhengqiu Li
Summary: Chemical proteomics is a powerful technology for studying uncharacterized proteins in the human proteome. A new protein-labeling strategy using nitrile oxide has been developed, which can efficiently react with target proteins. This method has shown excellent chemoselectivity and successfully characterized over 4000 cysteine residues, including KRAS G12C, demonstrating its complementary utility.
ACS CHEMICAL BIOLOGY
(2023)
Article
Chemistry, Medicinal
Yiying Wei, Xinxin Xu, Minchuan Jiang, Yongxing Wang, Yang Zhou, Zhen Wang, Zhang Zhang, Fengtao Zhou, Ke Ding
Summary: A new selective GSPT1 degrader was developed, which could effectively degrade GSPT1 and showed good selectivity in the global proteomic profiling study. The compound also displayed good antiproliferative activities and induced cell cycle arrest and apoptosis in U937 cells.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Shumin Lv, Fang Xu, Youlong Fan, Ke Ding, Zhengqiu Li
Summary: Due to the limited targets for drug development, triple-negative breast cancer (TNBC) is considered a challenging disease for chemotherapy. In this study, a set of novel electrophilic warheads was used to search for potential targets for TNBC in chemical proteomics studies. These warheads were found to modify not only highly nucleophilic residues but also weakly nucleophilic residues. Cys12 of Kirsten rat sarcoma (KRASG12C) was successfully labeled by cyclopropenone and cyclopropeniminium ions. Preliminary results showed moderate inhibitory activity against TNBC cells with these electrophile-based probes, and FABP5 was identified as a potential target for TNBC through further functional validation experiments.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Zuqin Wang, Jie Wang, Yongjin Wang, Shuang Xiang, Hengliang Zhou, Shukai Song, Xiaojuan Song, Zhengchao Tu, Yang Zhou, Ke Ding, Zhi-Min Zhang, Zhang Zhang, Xiaoyun Lu
Summary: This study focuses on the development of new type II TRK inhibitors to combat acquired resistance mutations. Compound 10g displayed excellent potency against TRK mutants and demonstrated strong inhibition of cell proliferation. The results provide a promising lead compound for pan-anticancer drug discovery.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
