Article
Oncology
Rahim Ullah, Qing Yin, Aidan H. Snell, Lixin Wan
Summary: The RAF-MEK-ERK signaling cascade is a well-characterized MAPK pathway that plays a critical role in cell proliferation and survival. Genetic alterations in this pathway are highly prevalent in human cancers and can lead to uncontrolled cell growth and tumor formation. The crosstalk between the RAF-MEK-ERK axis and other signaling pathways further enhances its proliferative potential in human cancers.
SEMINARS IN CANCER BIOLOGY
(2022)
Article
Biochemistry & Molecular Biology
William M. Marsiglia, Arthur Chow, Zaigham M. Khan, Liu He, Arvin C. Dar
Summary: This study presents a NanoBRET-based assay to quantify the direct target engagement of MEK inhibitors on MEK1 and its complexes with ARAF, BRAF, CRAF, KSR1 and KSR2 in living cells. The study reveals the preferences of MEK inhibitors among these complexes and their binding profiles. Furthermore, the assay can also report on the effect of pathogenic mutations on MEK inhibitor binding. These methods are important for screening compounds targeting specific complexes in the RAS-MAPK cascade.
NATURE CHEMICAL BIOLOGY
(2023)
Article
Multidisciplinary Sciences
Morgan R. Packer, Jillian A. Parker, Jean K. Chung, Zhenlu Li, Young Kwang Lee, Trinity Cookis, Hugo Guterres, Steven Alvarez, Md Amin Hossain, Daniel P. Donnelly, Jeffrey N. Agar, Lee Makowski, Matthias Buck, Jay T. Groves, Carla Mattos
Summary: Studies demonstrate that Raf-Ras binding domain (Raf-RBD) can induce Ras dimerization at low surface densities and in solution, with robust connections between two Raf-RBD D113 residues confirmed by molecular dynamics simulations. These results suggest that Raf-RBD binding and Ras dimerization occur together, forming a high-affinity signaling complex.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Article
Oncology
Sara J. Hamis, Yury Kapelyukh, Aileen McLaren, Colin J. Henderson, C. Roland Wolf, Mark A. J. Chaplain
Summary: The study developed a mechanistic mathematical model to describe the synergistic action of dabrafenib and trametinib on ERK activity in BRAFV600E-mutant melanoma cells, elucidating the molecular mechanism underlying vertical inhibition of the BRAF-MEK-ERK cascade.
BRITISH JOURNAL OF CANCER
(2021)
Article
Oncology
Aayoung Hong, Marco Piva, Sixue Liu, Willy Hugo, Shirley H. Lomeli, Vincent Zoete, Christopher E. Randolph, Zhentao Yang, Yan Wang, Jordan J. Lee, Skylar J. Lo, Lu Sun, Agustin Vega-Crespo, Alejandro J. Garcia, David B. Shackelford, Steven M. Dubinett, Philip O. Scumpia, Stephanie D. Byrum, Alan J. Tackett, Timothy R. Donahue, Olivier Michielin, Sheri L. Holmen, Antoni Ribas, Gatien Moriceau, Roger S. Lo
Summary: Combining type II RAF inhibitor with MEK inhibitor effectively prevents and overcomes acquired resistance in cancers with specific mutations, while also expanding memory and activated CD8(+) T cells. This combination therapy shows potential in broad cancer indications and may be further enhanced by exploring mechanisms of MAPK protein interactions and preserving tumor-infiltrating T cells.
Review
Biochemistry & Molecular Biology
Yanlin Song, Zhenfei Bi, Yu Liu, Furong Qin, Yuquan Wei, Xiawei Wei
Summary: Molecular target inhibitors have been approved for tumor treatment and mainly target cell proliferation and metabolism. The RAS-RAF-MEK-ERK pathway plays essential roles in cell functions and abnormal activation of this pathway leads to tumor development. In this review, the development and potential combinations of inhibitors targeting this pathway are discussed.
Article
Oncology
Da Wang, Fei Xiong, Guanhua Wu, Wenzheng Liu, Bing Wang, Yongjun Chen
Summary: The study found that in cholangiocarcinoma, miR-155-5p targets the 3' UTR of SOX1, activating the RAF/MEK/ERK pathway and promoting cancer progression.
CANCER CELL INTERNATIONAL
(2021)
Article
Oncology
Ying Zhang, Qian Lu, Nan Li, Ming Xu, Tatsuo Miyamoto, Jing Liu
Summary: Sulforaphane (SFN), a natural compound derived from broccoli, has been found to significantly inhibit migration and invasion of breast cancer cells by affecting cytoskeleton formation. SFN can also directly bind to RAF family proteins and inhibit phosphorylation of the signaling pathway. These findings suggest that SFN has the potential to be used as a therapeutic drug to inhibit breast cancer cell metastasis.
Article
Oncology
Shuai Wang, Xinyan Zhang, Houfa Ning, Senyi Dong, Guangzhi Wang, Ruimei Sun
Summary: This study discovered elevated levels of B7-H3 in breast cancer, which were associated with poor prognosis. B7-H3 can promote lung metastasis in breast cancer through activation of the Raf/MEK/ERK axis.
BREAST CANCER RESEARCH AND TREATMENT
(2022)
Review
Oncology
Renee Barbosa, Lucila A. Acevedo, Ronen Marmorstein
Summary: The RAS-RAF-MEK-ERK pathway is crucial for cell proliferation, differentiation, and survival, with mutations in upstream proteins RAS and RAF contributing to many human cancers and nearly all cutaneous melanomas. Targeting terminal kinases in the MAPK cascade has shown promise in overcoming drug resistance and improving treatment options for patients with MAPK-aberrant cancers.
MOLECULAR CANCER RESEARCH
(2021)
Review
Pharmacology & Pharmacy
Yunli Huang, Yongqi Zhen, Yanmei Chen, Shaoguang Sui, Lan Zhang
Summary: This article provides a comprehensive review of the interplay between the RAS/RAF/MEK/ERK signaling pathway and autophagy, as well as their application in cancer therapy. The impact of small molecule inhibitors targeting this pathway on autophagy is discussed, and the advantages and limitations of combining these inhibitors with autophagy inhibitors are explored.
BIOCHEMICAL PHARMACOLOGY
(2023)
Article
Virology
Chengyuan Wu, Guangyan Zhu, Fang Qiu, Fuli Ren, Binbin Lin, Dingyu Zhang, Qingyu Yang, Chaolin Huang
Summary: EV71 is a serious threat to human health and there is currently no effective drug for its treatment. PLX8394, a RAF inhibitor, has been found to have high antiviral activity against EV71 in vitro and also exhibits broad-spectrum antiviral activity against enteroviruses. In a mouse model, PLX8394 provided significant protection against EV71 infection by reducing viral load and relieving inflammation through inhibiting the RAF/MEK/ERK signaling pathway.
Article
Immunology
Helen Hoffmann, Marina Ebensperger, Annika Schoensiegel, Hazem Hamza, Julia Koch-Heier, Andre Schreiber, Stephan Ludwig, Michael Schindler, Oliver Planz
Summary: The urgent need for broad-spectrum antivirals has been highlighted by the COVID-19 pandemic. In this study, the antiviral efficacy of zapnometinib was compared between influenza A virus (IAV) and SARS-CoV-2, revealing that IAV is more susceptible to treatment with zapnometinib compared to SARS-CoV-2.
FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Jakob Fleischmann, Andreas Feichtner, Louis DeFalco, Valentina Kugler, Selina Schwaighofer, Roland G. Huber, Eduard Stefan
Summary: Mutations in the MAPK signaling pathway can lead to abnormal activation of protein kinases, with targeted MEK inhibition causing qualitative changes in carcinogenic MAPK signals. By phosphorylating MEK1 at specific sites, RAF kinases trigger conformational changes that enable substrate phosphorylation. Allosterically acting MEK inhibitors can reverse the conformational changes induced by phosphorylation, indicating their potential efficacy in cancer therapy.
Article
Oncology
Liang Yan, Bo Tu, Jun Yao, Jing Gong, Alessandro Carugo, Christopher A. Bristow, Qiuyun Wang, Cihui Zhu, Bingbing Dai, Ya'an Kang, Leng Han, Ningping Feng, Yanqing Jin, Jason Fleming, Timothy P. Heffernan, Wantong Yao, Haoqiang Ying
Summary: The study highlights the critical role of glucose metabolism in resistance to MAPK inhibition in KRAS-driven pancreatic cancer, suggesting a potential therapeutic approach in targeting this aggressive disease.
Article
Medicine, Research & Experimental
Jun-Jae Chung, Tobias B. Huber, Markus Goedel, George Jarad, Bjoern Hartleben, Christopher Kwoh, Alexander Keil, Aleksey Karpitskiy, Jiancheng Hu, Christine J. Huh, Marina Cella, Richard W. Gross, Jeffrey H. Miner, Andrey S. Shaw
JOURNAL OF CLINICAL INVESTIGATION
(2015)
Article
Immunology
Xiaolu Xu, Xinxin Wang, Elizabeth M. Todd, Emily R. Jaeger, Jennifer L. Vella, Olivia L. Mooren, Yunfeng Feng, Jiancheng Hu, John A. Cooper, Sharon Celeste Morley, Yina H. Huang
JOURNAL OF IMMUNOLOGY
(2016)
Article
Biochemistry & Molecular Biology
Jimin Yuan, Wan Hwa Ng, Jiajun Yap, Brandon Chia, Xuchao Huang, Mei Wang, Jiancheng Hu
JOURNAL OF BIOLOGICAL CHEMISTRY
(2018)
Article
Biochemistry & Molecular Biology
Jimin Yuan, Wan Hwa Ng, Paula Y. P. Lam, Yu Wang, Hongping Xia, Jiajun Yap, Shou Ping Guan, Ann S. G. Lee, Mei Wang, Manuela Baccarini, Jiancheng Hu
Article
Biochemistry & Molecular Biology
Jimin Yuan, Wan Hwa Ng, Zizi Tian, Jiajun Yap, Manuela Baccarini, Zhongzhou Chen, Jiancheng Hu
Article
Cell & Tissue Engineering
Zhenbo Han, Ying Yu, Juan Xu, Zhengyi Bao, Zihang Xu, Jiancheng Hu, Meixi Yu, Djibril Bamba, Wenya Ma, Fengzhi Ding, Lai Zhang, Mengyu Jin, Gege Yan, Qi Huang, Xiuxiu Wang, Bingjie Hua, Fan Yang, Yuan Li, Lei Lei, Nan Cao, Zhenwei Pan, Benzhi Cai
Article
Oncology
Aldo Prawira, Prabhakaran Munusamy, Jimin Yuan, Claire Hian Tzer Chan, Geok Ling Koh, Timothy Wai Ho Shuen, Jiancheng Hu, Yoon Sim Yap, Min Han Tan, Peter Ang, Ann Siew Gek Lee
BREAST CANCER RESEARCH AND TREATMENT
(2019)
Article
Endocrinology & Metabolism
Siao Ting Chong, Khee Ming Tan, Catherine Y. L. Kok, Shou Ping Guan, Siang Hui Lai, Cindy Lim, Jiancheng Hu, Charles Sturgis, Charis Eng, Paula Y. P. Lam, Joanne Ngeow
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM
(2019)
Review
Cell Biology
Ufuk Degirmenci, Mei Wang, Jiancheng Hu
Article
Oncology
Xiang Li, Chen Zhang, Ting Zhao, Zhongping Su, Mengjing Li, Jiancheng Hu, Jianfei Wen, Jiajia Shen, Chao Wang, Jinshun Pan, Xianmin Mu, Tao Ling, Yingchang Li, Hao Wen, Xiaoren Zhang, Qiang You
JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH
(2020)
Review
Oncology
Jimin Yuan, Xiaoduo Dong, Jiajun Yap, Jiancheng Hu
JOURNAL OF HEMATOLOGY & ONCOLOGY
(2020)
Article
Multidisciplinary Sciences
Jiajun Yap, R. N. V. Krishna Deepak, Zizi Tian, Wan Hwa Ng, Kah Chun Goh, Alicia Foo, Zi Heng Tee, Manju Payini Mohanam, Yuen Rong M. Sim, Ufuk Degirmenci, Paula Lam, Zhongzhou Chen, Hao Fan, Jiancheng Hu
Summary: The study identified a novel group of oncogenic BRAF mutants with stabilized R-spines, leading to strong resistance to RAF inhibitors, which is not due to dimer affinity but rather stability of the R-spine.
Review
Oncology
Ufuk Degirmenci, Jiajun Yap, Yuen Rong M. Sim, Shiru Qin, Jiancheng Hu
Summary: The first-generation RAF inhibitors have shown promising results in treating cancers with BRAF(V600E) mutations, but face challenges of rapid drug resistance and intrinsic resistance in cancers with hyperactive RAS. To address these issues, second-generation RAF inhibitors are being developed for improved efficacy.
CANCER DRUG RESISTANCE
(2021)
Meeting Abstract
Oncology
Siao Ting Chong, Catherine Y. Kok, Khee Ming Tan, Shou Ping Guan, Siang Hui Lai, Cindy Lim, Jiancheng Hu, Charles Sturgis, Charis Eng, Paula Y. Lam, Joanne Ngeow