Article
Chemistry, Analytical
John C. Tran, Thomas Hunsaker, Christina Bell, Taylur P. Ma, Emily Chan, Pablo Saenz-Lopez Larrocha, Kelsey Homyk, Liling Liu, Hank La, Jialin Mao, Cecile C. de la Cruz, Kebing Yu, Maureen Beresini, William F. Forrest, Yang Xiao, Anne Jang, Natalia Samus, Nicholas Dupuis Stesco, Marija Mentinova, Stephane Parent, Gwenael Pottiez, Michael Schirm, Hans E. Purkey, Yichin Liu, Mark Merchant
Summary: The growing opportunities for covalent drug inhibitors, such as KRAS G12C inhibitors, have driven the need for mass spectrometry methods to measure therapeutic drug activity in vivo efficiently. In this study, an automated and integrated sample preparation method was described to measure the activity levels of KRAS G12C drug inhibitor alkylation from complex tumor samples. The method showed reliable results with low variation, enabling a better understanding of the relationship between KRAS G12C target occupancy and therapeutic effects.
ANALYTICAL CHEMISTRY
(2023)
Article
Multidisciplinary Sciences
Yulei Zhao, Yonina R. Murciano-Goroff, Jenny Y. Xue, Agnes Ang, Jessica Lucas, Trang T. Mai, Arnaud F. Da Cruz Paula, Anne Y. Saiki, Deanna Mohn, Pragathi Achanta, Ann E. Sisk, Kanika S. Arora, Rohan S. Roy, Dongsung Kim, Chuanchuan Li, Lee P. Lim, Mark Li, Amber Bahr, Brian R. Loomis, Elisa de Stanchina, Jorge S. Reis-Filho, Britta Weigelt, Michael Berger, Gregory Riely, Kathryn C. Arbour, J. Russell Lipford, Bob T. Li, Piro Lito
Summary: Resistance to KRAS(G12C) inhibitors demonstrates a heterogeneous pattern with multiple subclonal events emerging during treatment. Co-targeting of ERK signaling intermediates can enhance the antiproliferative effect of G12C inhibitor treatment in models with acquired RAS or BRAF mutations.
Editorial Material
Oncology
Christina Guo, Udai Banerji
Summary: KRAS mutations play a critical role in cancer, with drugs targeting KRAS(G12C) mutations showing potential efficacy. Clinical trials targeting non-G12C mutated KRAS driven cancers with the dual RAF-MEK inhibitor VS-6766 have shown early single agent activity.
BRITISH JOURNAL OF CANCER
(2021)
Article
Pharmacology & Pharmacy
Xing-Duo Dong, Meng Zhang, Chao-Yun Cai, Qiu-Xu Teng, Jing-Quan Wang, Yi-Ge Fu, Qingbin Cui, Ketankumar Patel, Dong-Tao Wang, Zhe-Sheng Chen
Summary: This study investigated the potential drug resistance mechanism of the KRAS-G12C inhibitor ARS-1620 associated with ABCB1. The findings indicated that ARS-1620 could be competitively pumped out by ABCB1 in cancer cells and significantly stimulated the ATPase activity of ABCB1. These findings suggest that the potential influence of ARS-1620-related cancer therapy on ABCB1-overexpressing cancer cells should be considered in future clinical applications.
FRONTIERS IN PHARMACOLOGY
(2022)
Article
Chemistry, Organic
Jie Xu, Ngiap-Kie Lim, Jacob C. Timmerman, Jeff Shen, Kyle Clagg, Ugo Orcel, Raphael Bigler, Etienne Trachsel, Roland Meier, Nicholas A. White, Johannes A. Burkhard, Lauren E. Sirois, Qingping Tian, Remy Angelaud, Stephan Bachmann, Haiming Zhang, Francis Gosselin
Summary: A chromatography-free asymmetric synthesis of GDC-6036 was achieved via a highly atroposelective Negishi coupling reaction. The key intermediate, (Ra)-3, was obtained through the coupling of aminopyridine 5 and quinazoline 6b catalyzed by 0.5 mol% [Pd(cin)Cl]2 and 1 mol% (R,R)-Chiraphite. The final product, high-purity GDC-6036, was obtained through controlled acrylamide installation and adipate salt formation.
Review
Pharmacology & Pharmacy
Tetsuo Tani, Shunsuke Kitajima, Ella B. Conway, Erik H. Knelson, David A. Barbie
Summary: This paper reviews the impact of KRAS mutations on tumorigenesis and discusses the potential of KRAS-G12C covalent inhibitors in clinical trials. Therapeutic targeting of KRAS-G12C and its effects on the tumor immune microenvironment are crucial for promoting anti-tumor immunity and improving response durability.
EXPERT OPINION ON THERAPEUTIC TARGETS
(2021)
Article
Oncology
Thomas McFall, Michael Trogdon, Anita C. Guizar, John F. Langenheim, Laura Sisk-Hackworth, Edward C. Stites
Summary: The combination of KRAS G12C inhibitors with EGFR inhibitors has shown consistent benefits, including inhibiting both wild-type and mutant RAS.
NPJ PRECISION ONCOLOGY
(2022)
Review
Pharmacology & Pharmacy
Junmin Zhang, Juanhong Zhang, Qing Liu, Xing-Xing Fan, Elaine Lai-Han Leung, Xiao-Jun Yao, Liang Liu
Summary: KRAS mutations are common in carcinoma, and KRAS G12C inhibitors have exhibited significant clinical responses. However, resistance mechanisms to these inhibitors are diverse and further research is needed.
PHARMACOLOGY & THERAPEUTICS
(2022)
Article
Biochemistry & Molecular Biology
Ling Li, Yinrong Wu, Zichao Yang, Chenglong Xu, Huiting Zhao, Jin Liu, Jingxuan Chen, Jianjun Chen
Summary: A series of KRAS G12C-targeting PROTACs were designed and synthesized, with compound KP-14 showing the highest degrading capability in NCI-H358 cancer cells. KP-14 bound to KRAS G12C through the acrylamide warhead and recruited E3 ligase CRBN, leading to rapid and sustained degradation of KRAS G12C and suppression of the MAPK signaling pathway in cancer cells.
BIOORGANIC CHEMISTRY
(2021)
Article
Oncology
Ayako Nakayama, Takeyuki Nagashima, Yoshihiro Nishizono, Kazuyuki Kuramoto, Kenichi Mori, Kazuya Homboh, Masatoshi Yuri, Masashi Shimazaki
Summary: ASP2453 is a potential therapeutic agent for KRAS G12C-mutated cancer, showing improved anti-tumour effects of targeted agents and immune checkpoint inhibitors, with faster binding kinetics and stronger inhibitory effects on KRAS activation and cell proliferation compared to AMG 510.
BRITISH JOURNAL OF CANCER
(2022)
Review
Oncology
Alfredo Addeo, Giuseppe Luigi Banna, Alex Friedlaender
Summary: This article discusses the role of KRAS in non-small cell lung cancer, including research on the mechanisms of resistance to KRAS G12C inhibitors and ways to overcome them. Additionally, advances in the treatment of non-small cell lung cancer, particularly with two therapeutic breakthroughs related to immune checkpoint inhibitors and oncogenic driver mutations targeting, are introduced.
Editorial Material
Oncology
Amanda R. Moore, Shiva Malek
Summary: The study found that sotorasib provides clinical benefit for KRAS p.G12C-mutated non-small-cell lung cancer (NSCLC) and provides mechanistic insights into acquired resistance to KRAS(G12C)-specific inhibition.
Article
Medicine, General & Internal
Marwan G. Fakih, Lisa Salvatore, Taito Esaki, Dominik P. Modest, David P. Lopez-Bravo, Julien Taieb, Michalis V. Karamouzis, Erika Ruiz-Garcia, Tae-Won Kim, Yasutoshi Kuboki, Fausto Meriggi, David Cunningham, Kun-Huei Yeh, Emily Chan, Joseph Chao, Yaneth Saportas, Qui Tran, Chiara Cremolini, Filippo Pietrantonio
Summary: In this study, the combination of KRAS G12C inhibitor sotorasib and EGFR inhibitor panitumumab showed longer progression-free survival compared to standard treatment in patients with chemorefractory metastatic colorectal cancer.
NEW ENGLAND JOURNAL OF MEDICINE
(2023)
Article
Multidisciplinary Sciences
Tereza Vaclova, Atanu Chakraborty, James Sherwood, Sarah Ross, Danielle Carroll, J. Carl Barrett, Julian Downward, Elza C. de Bruin
Summary: The study investigates the co-occurrence of additional KRAS mutations with KRAS G12C in non-small cell lung cancer (NSCLC) tumors and its impact on cellular response to G12C-specific inhibitors. The results show that KRAS c.35G>T mutation most frequently co-occurred with KRAS G12C and led to cellular resistance to G12C inhibitors. Therefore, comprehensive genotyping of KRAS tumors is necessary for optimal patient selection for treatment with a KRAS G12C inhibitor.
SCIENTIFIC REPORTS
(2022)
Review
Oncology
Ai Yang, Min Li, Mingzhi Fang
Summary: This review summarizes the progress in the development of direct KRAS G12C mutation inhibitors, current relevant drugs under study, and challenges to be considered in future research.
PATHOLOGY & ONCOLOGY RESEARCH
(2021)
Article
Cell Biology
Ying Yang, Damian Gatica, Xu Liu, Runliu Wu, Rui Kang, Daolin Tang, Daniel J. Klionsky
Summary: This study reports the role of uORF-mediated translational control in regulating multiple Atg proteins in yeast and human cells. These findings suggest that uORF-mediated translational control is a widely used mechanism among ATG genes and provide a model for how some ATG genes bypass translational suppression under stress conditions to maintain proper autophagy levels.
Article
Cell Biology
Jiao Liu, Yang Liu, Yuan Wang, Changfeng Li, Yangchun Xie, Daniel J. Klionsky, Rui Kang, Daolin Tang
Summary: TMEM164 plays a key role in mediating autophagosome formation during iron-dependent ferroptosis, promoting cell death. High expression of TMEM164 is associated with improved survival and increased immune cell infiltration.
Article
Biochemistry & Molecular Biology
Fangquan Chen, Xiutao Cai, Rui Kang, Jiao Liu, Daolin Tang
Summary: Autophagy determines cell fate in response to environmental stresses and its dependence in cell death signals and mechanisms are still unclear. The discovery of autophagy-dependent ferroptosis provides insights into the relationship between aberrant degradation pathways and excessive lipid peroxidation in driving regulated cell death.
ANTIOXIDANTS & REDOX SIGNALING
(2023)
Article
Cell Biology
Liangchun Yang, Fanghua Ye, Jiao Liu, Daniel J. Klionsky, Daolin Tang, Rui Kang
Summary: This study reveals that extracellular SQSTM1 acts as a mediator of acute pancreatitis (AP) by enhancing sensitivity to autophagy-dependent ferroptotic cell death. High levels of serum SQSTM1 are found in AP patients and mice. Administration of SQSTM1-neutralizing antibodies protects mice against experimental AP.
Article
Cell Biology
Qian Xue, Ding Yan, Xi Chen, Xiaofen Li, Rui Kang, Daniel J. J. Klionsky, Guido Kroemer, Xin Chen, Daolin Tang, Jinbao Liu
Summary: Ferroptosis is an iron-dependent regulated cell death characterized by lipid peroxidation and membrane damage. Copper promotes ferroptotic cell death by inducing autophagic degradation of GPX4. These findings provide new insights into the connection between metal stress and autophagy-dependent cell death.
Article
Cell Biology
Fangquan Chen, Shan Zhu, Rui Kang, Daolin Tang, Jiao Liu
Summary: In this study, the researchers identified ATP6V0D1 as a direct target of JTC801, which drives alkaliptosis in human PDAC cells. The interaction between ATP6V0D1 and STAT3 increases STAT3 expression and activity, maintaining lysosome homeostasis. Inhibition of STAT3 restores the sensitivity of ATP6V0D1-deficient cells to alkaliptosis. Furthermore, high expression of ATP6V0D1 correlates with prolonged survival in PDAC patients.
Article
Biochemistry & Molecular Biology
Ruochan Chen, Ju Zou, Rui Kang, Daolin Tang
Summary: HMGB1 is a redox-sensitive protein that regulates stress responses, cell death, and inflammatory diseases. Understanding its role in cellular redox homeostasis is crucial for deciphering cellular functions and pathological manifestations.
ANTIOXIDANTS & REDOX SIGNALING
(2023)
Article
Biochemistry & Molecular Biology
Daolin Tang, Rui Kang
Summary: Over the past decade, research has focused on understanding oxidative cell death, particularly the transition from oxytosis to ferroptosis. Oxytosis, a form of nerve cell death induced by glutamate, was associated with intracellular glutathione depletion and inhibition of cystine uptake. The term ferroptosis was coined during a compound screening in 2012 and is induced by inhibitors of system xc(-) and GPX4. This article reviews the significant findings, models, and mechanisms of ferroptosis, and discusses its implications in various pathological conditions.
ANTIOXIDANTS & REDOX SIGNALING
(2023)
Article
Biochemistry & Molecular Biology
Yang Liu, Yuan Wang, Zhi Lin, Rui Kang, Daolin Tang, Jiao Liu
Summary: SLC25A22 acts as a metabolic repressor of ferroptosis by producing glutathione and monounsaturated fatty acids, providing a previously unrecognized defense pathway against ferroptotic cell death.
ANTIOXIDANTS & REDOX SIGNALING
(2023)
Review
Cell Biology
Yangchun Xie, Rui Kang, Daniel J. Klionsky, Daolin Tang
Summary: Selenoprotein GPX4 is the main oxidoreductase that uses glutathione to scavenge lipid peroxidation products. It has three isoforms with distinct expression patterns and its loss can trigger various forms of cell death and inflammation. GPX4's interaction with autophagy pathway modulates cell fate in response to oxidative stress. Impairment of GPX4 function is implicated in various diseases. Furthermore, a specific mutation in GPX4 is associated with a rare and fatal disease in newborns. This article discusses the roles of GPX4 in cell death, autophagy, and disease.
Editorial Material
Biotechnology & Applied Microbiology
Ruoxi Zhang, Rui Kang, Daolin Tang
Summary: The balance of oxidants and antioxidants, known as redox homeostasis, is crucial for cell function. Disruption of redox homeostasis is linked to the development and treatment of various diseases, including cancer. Recent studies have shown that both oxidative and reductive stress can trigger regulated cell death, such as disulfidptosis and pyroptosis, in cancer and immune cells. Exploring the relationship between oxidative and reductive cell death could lead to novel disease treatments.
CANCER GENE THERAPY
(2023)
Article
Oncology
Ruoxi Zhang, Rui Kang, Daolin Tang
Summary: Ferroptosis is a regulated cell death process triggered by excessive lipid peroxidation, leading to plasma membrane damage and the release of damage-associated molecular patterns. It has gained attention in cancer research, specifically in gastrointestinal (GI) cancers, due to its unique mechanism compared to other forms of regulated cell death. Exploring the role of ferroptosis in GI cancers may offer new treatment strategies for overcoming drug resistance caused by defects in apoptotic pathways.
Review
Immunology
Daolin Tang, Guido Kroemer, Rui Kang
Summary: Ferroptosis is a regulated cell death process that occurs when there is an accumulation of toxic lipid peroxides, particularly in the plasma membrane, due to iron-dependency. While it is crucial for maintaining overall health, it can also lead to tissue damage and pathological conditions. Understanding the immune characteristics of ferroptosis in infection, sterile inflammation, and tumor immunity is important for developing therapeutic strategies.
IMMUNOLOGICAL REVIEWS
(2023)
Review
Immunology
Daolin Tang, Rui Kang, Herbert J. Zeh, Michael T. Lotze
Summary: Fifty years since the discovery of HMGB1 protein, its physiological and pathological roles have been extensively studied. This Review covers the structure, localization, and functions of HMGB1 in immune responses, including historical foundations and recent advances.
NATURE REVIEWS IMMUNOLOGY
(2023)
Correction
Biotechnology & Applied Microbiology
Jiao Liu, Rui Kang, Daolin Tang
CANCER GENE THERAPY
(2023)
