Article
Multidisciplinary Sciences
Andrey V. Reshetnyak, Paolo Rossi, Alexander G. Myasnikov, Munia Sowaileh, Jyotidarsini Mohanty, Amanda Nourse, Darcie J. Miller, Irit Lax, Joseph Schlessinger, Charalampos G. Kalodimos
Summary: ALK is a receptor tyrosine kinase that regulates important functions in the central nervous system, and mutations in this gene may lead to neuroblastoma. Research has revealed a mechanism of RTK activation that allows dimerization by different ligands, with the complex architecture of the receptor-ligand complex playing a key role in this process.
Review
Immunology
Ye Guo, Hanfei Guo, Yongfei Zhang, Jiuwei Cui
Summary: Alterations in the ALK gene are crucial in the development of various tumors, and targeted therapy has transformed the treatment approach. However, resistance remains a challenge. ALK gene variants have a significant impact on the tumor immune microenvironment, suggesting potential clinical applications for immunotherapy targeting ALK-altered tumors.
FRONTIERS IN IMMUNOLOGY
(2022)
Article
Medicine, General & Internal
Shih-Lung Chen, Kai-Chieh Chan
Summary: ALCL is a rare form of non-Hodgkin's lymphoma, especially when it occurs in the external auditory canal (EAC). Diagnosis of ALCL in the EAC region can be challenging, but a combination of imaging, histopathological examination and IHC staining can confirm the presence of the disease. Treatment options include radiotherapy, chemoradiotherapy, and targeted therapies like Brentuximab vedotin for ALK-positive ALCL.
Article
Oncology
Giulia Mura, Elif Karaca Atabay, Matteo Menotti, Cinzia Martinengo, Chiara Ambrogio, Gloria Giacomello, Maddalena Arigoni, Martina Olivero, Raffaele A. Calogero, Roberto Chiarle, Claudia Voena
Summary: Anaplastic Large Cell Lymphoma (ALCL) is driven by the chimeric tyrosine kinase NPM-ALK, which downregulates the expression of CD45 via STAT3 and acts as a rheostat of ALK oncogenic signaling and resistance to TKI treatment. CD45 is a key regulator of T cell activation and cytokine responses through the JAK/STAT pathway. In ALK+ ALCL, NPM-ALK inhibits T cell molecules expression and activates surrogate TCR signaling. Inhibition of NPM-ALK kinase activity leads to increased expression of CD45RO isoform. Knocking-out CD45 results in increased resistance to ALK TKI treatment.
FRONTIERS IN ONCOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Masaaki Machino, Yuanhao Gong, Tomoya Ozaki, Yuji Suzuki, Eri Watanabe, Shiro Imagama, Kenji Kadomatsu, Kazuma Sakamoto
Summary: The study demonstrates that dermatan sulphate (DS) interacts directly with the extracellular domain of ALK protein and induces its activation, similar to the role of heparan sulphate (HS). The findings reveal the impact of glycans as signaling molecules on the ALK signaling pathway.
JOURNAL OF BIOCHEMISTRY
(2021)
Article
Chemistry, Multidisciplinary
Luca Mologni, Sebastien Tardy, Alfonso Zambon, Alexandre Orsato, William H. Bisson, Monica Ceccon, Michela Viltadi, Joseph D'Attoma, Sara Pannilunghi, Vito Vece, Jerome Bertho, Peter Goekjian, Leonardo Scapozza, Carlo Gambacorti-Passerini
Summary: A series of azacarbazole inhibitors were designed, synthesized, and evaluated, with compound 149 showing selective inhibition of both native and drug-resistant mutants of the ALK kinase. The three-dimensional structure of a 149:ALK-KD cocrystal revealed extensive interaction through the hinge region and the catalytic lysine 1150, demonstrating its potential as a promising therapeutic candidate.
Article
Nutrition & Dietetics
Simona Dedoni, Maria Scherma, Chiara Camoglio, Carlotta Siddi, Walter Fratta, Paola Fadda
Summary: The expression of ALK receptor is reduced in rats with activity-based anorexia, indicating a potential involvement of ALK receptor in the pathophysiology of anorexia nervosa.
Review
Pharmacology & Pharmacy
Kajetan Kielbowski, Justyna Zychowska, Rafal Becht
Summary: This review summarizes the efficacy and safety profile of ALK inhibitors, describes off-target anticancer effects, and discusses resistance mechanisms in the context of personalized oncology.
FRONTIERS IN PHARMACOLOGY
(2023)
Article
Pharmacology & Pharmacy
Yihan Liu, Chen Chen, Chencheng Rong, Xucheng He, Li Chen
Summary: This study analyzed real-world data from the FAERS to investigate cardiac disorders associated with ALK-TKIs. The results showed that cardiac adverse events were more prevalent in patients aged 45 or older, with a higher proportion among women. Cardiac arrhythmia, especially bradycardia, was a common adverse event, and certain drugs like crizotinib and lorlatinib showed positive signals in cardiac disorders. The study also identified potential new adverse drug reactions, such as myocarditis caused by ceritinib and cardiomyopathy caused by lorlatinib. The findings highlight the importance of monitoring and further research on the cardiac safety of ALK-TKIs.
FRONTIERS IN PHARMACOLOGY
(2022)
Review
Oncology
Xin-Rui Zhang, Pham-Ngoc Chien, Sun-Young Nam, Chan-Yeong Heo
Summary: Anaplastic large cell lymphoma is a rare disease with four subtypes that differ in clinical symptoms, gene changes, prognosis, and treatment.
Article
Multidisciplinary Sciences
Keshav Patil, Earl Joseph Jordan, Jin H. Park, Krishna Suresh, Courtney M. Smith, Abigail A. Lemmon, Yael P. Mosse, Mark A. Lemmon, Ravi Radhakrishnan
Summary: Kinases are crucial in various cellular processes and commonly mutated in cancer, their activation status can be effectively predicted through computational studies despite mutations occurring throughout the kinase domain. The results provide insights into convergent activation mechanisms in majority of studied mutations.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Article
Oncology
Takafumi Fukui, Motoko Tachihara, Tatsuya Nagano, Kazuyuki Kobayashi
Summary: Anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC) has made significant progress in recent years with the development of multiple tyrosine kinase inhibitors (TKIs) targeting ALK. Clinical trials of novel ALK-TKIs, angiogenesis inhibitors, immune checkpoint inhibitors, and chemotherapy are ongoing, and tissue and liquid biopsy are being explored as methods to investigate resistance mechanisms. This manuscript aims to provide information on these recent clinical trials and propose a treatment algorithm for ALK-rearranged advanced NSCLC.
Article
Biochemistry & Molecular Biology
Mohd Saeed, Nawaf Alshammari, Amir Saeed, Asma Ayyed AL-Shammary, Nadiyah M. Alabdallah, Irfan Ahmad, Farrukh Aqil
Summary: Lung cancer is a major global public health issue and the leading cause of cancer-related deaths. In this study, computational predictions were used to identify the potential of cucurbitacins as inhibitors for the ALK protein in lung cancer. The results suggest that cucurbitacin B has the potential to act as a potent natural inhibitor against ALK and may be a valuable treatment option for lung cancer.
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
(2023)
Article
Immunology
Annkristin Heine, Stefanie Andrea Erika Held, Solveig Nora Daecke, Chrystel Flores, Peter Brossart
Summary: This study investigates the immunosuppressive effects of two different ALK inhibitors on dendritic cells. The results show that crizotinib significantly suppresses the activation, migration, and cytokine production of dendritic cells, while alectinib has lesser immunosuppressive effects.
FRONTIERS IN IMMUNOLOGY
(2023)
Review
Urology & Nephrology
Marco Bonilla, Kenar D. Jhaveri, Hassan Izzedine
Summary: This review introduces the main treatment method, ALK inhibitors, for NSCLC patients with ALK gene rearrangement or ROS1 oncogene fusion. However, the toxic side effects of these drugs, especially those related to the kidneys, need to be taken seriously.
CLINICAL KIDNEY JOURNAL
(2022)
Article
Cell Biology
Heather Kalish, Carleen Klumpp-Thomas, Sally Hunsberger, Holly Ann Baus, Michael P. Fay, Nalyn Siripong, Jing Wang, Jennifer Hicks, Jennifer Mehalko, Jameson Travers, Matthew Drew, Kyle Pauly, Jacquelyn Spathies, Tran Ngo, Kenneth M. Adusei, Maria Karkanitsa, Jennifer A. Croker, Yan Li, Barry Graubard, Lindsay Czajkowski, Olivia Belliveau, Cheryl Chairez, Kelly R. Snead, Peter Frank, Anandakumar Shunmugavel, Alison Han, Luca T. Giurgea, Luz Angela Rosas, Rachel Bean, Rani Athota, Adriana Cervantes-Medina, Monica Gouzoulis, Brittany Heffelfinger, Shannon Valenti, Rocco Caldararo, Michelle M. Kolberg, Andrew Kelly, Reid Simon, Saifullah Shafiq, Vanessa Wall, Susan Reed, Eric W. Ford, Ravi Lokwani, John-Paul Denson, Simon Messing, Sam G. Michael, William Gillette, Robert P. Kimberly, Steven E. Reis, Matthew D. Hall, Dominic Esposito, Matthew J. Memoli, Kaitlyn Sadtler
Summary: The study analyzed undiagnosed SARS-CoV-2 infections in the United States and found a high prevalence rate, with different seropositivity estimates among various racial, age, gender, ethnic, and urban/rural groups. Data indicated that as of mid-July 2020, there were an estimated 16.8 million undiagnosed infections in the United States, with 4.8 undiagnosed cases for every diagnosed case of COVID-19.
SCIENCE TRANSLATIONAL MEDICINE
(2021)
Article
Multidisciplinary Sciences
Chun Hu, Carlos A. Leche, Anatoly Kiyatkin, Zhaolong Yu, Steven E. Stayrook, Kathryn M. Ferguson, Mark A. Lemmon
Summary: The epidermal growth factor receptor (EGFR) frequently mutates in human cancer, and is an important therapeutic target. However, EGFR inhibitors have limited effectiveness in glioblastoma multiforme (GBM) due to exclusive mutations in the extracellular region. This study reveals that GBM mutations impair EGFR's ability to distinguish between activating ligands, which may have implications for therapeutic targeting.
Article
Chemistry, Medicinal
Maria-Elena Liosi, Joseph A. Ippolito, Sean P. Henry, Stefan G. Krimmer, Ana S. Newton, Kara J. Cutrona, Rene A. Olivarez, Jyotidarsini Mohanty, Joseph Schlessinger, William L. Jorgensen
Summary: This study aimed to develop binders that selectively target the JH2 domain of JAK2 and test their ability to modulate JAK2 activity in cells. Through computational design, synthesis, binding affinity measurements, permeability measurements, crystallography, and cell assays, the researchers successfully optimized a diaminotriazole compound that can inhibit the activity of JAK2 in cells.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Review
Biochemistry & Molecular Biology
Joshua B. Sheetz, Mark A. Lemmon
Summary: Progress has been made in understanding the role of pseudokinases in biology and disease over the past decade. Despite lacking key catalytic residues, pseudokinases show striking similarity to their kinase relatives. Recent structural data suggest that both pseudokinases and bona fide kinases maintain distinct conformational states, which play a crucial role in their function. Understanding and targeting the conformational toggle in pseudokinases could have implications for disease treatment.
TRENDS IN BIOCHEMICAL SCIENCES
(2022)
Article
Chemistry, Medicinal
Sean P. Henry, Maria-Elena Liosi, Joseph A. Ippolito, Kara J. Cutrona, Stefan G. Krimmer, Ana S. Newton, Joseph Schlessinger, William L. Jorgensen
Summary: The study explored the potential of modulating JAK2 kinase activity by binding to the ATP site in JH2 domain and developed compounds with nanomolar affinity and high selectivity for JAK2 JH2 domain. Crystal structure analysis revealed the binding mechanism of these compounds with JAK2 JH2, offering a new platform for seeking molecules to regulate JAK2 signaling.
ACS MEDICINAL CHEMISTRY LETTERS
(2022)
Article
Multidisciplinary Sciences
Lei Peng, Yingxia Hu, Madeleine C. Mankowski, Ping Ren, Rita E. Chen, Jin Wei, Min Zhao, Tongqing Li, Therese Tripler, Lupeng Ye, Ryan D. Chow, Zhenhao Fang, Chunxiang Wu, Matthew B. Dong, Matthew Cook, Guilin Wang, Paul Clark, Bryce Nelson, Daryl Klein, Richard Sutton, Michael S. Diamond, Craig B. Wilen, Yong Xiong, Sidi Chen
Summary: This study reports the development of monoclonal antibodies (mAbs) that effectively neutralize SARS-CoV-2 variants of concern. By using high-throughput single cell sequencing, the researchers identified two highly potent mAb clones with strong neutralizing activity against SARS-CoV-2 and its emerging variants. Cryo-EM structures revealed the distinct epitopes, binding patterns, and conformations of these neutralizing antibodies. The lead clones also showed potent efficacy in vivo against authentic SARS-CoV-2 in both preventive and therapeutic settings. Furthermore, a humanized antibody was generated and showed strong potency against both the original virus and the B.1.617.2 Delta variant. These mAbs expand the repertoire of therapeutics against SARS-CoV-2 and emerging variants.
NATURE COMMUNICATIONS
(2022)
Article
Multidisciplinary Sciences
Nathan M. Ennist, Zhenyu Zhao, Steven E. Stayrook, Bohdana M. Discher, P. Leslie Dutton, Christopher C. Moser
Summary: Natural photosynthetic protein complexes are complex and fragile, making reengineering efforts challenging. In this study, researchers developed a simplified artificial photosynthetic reaction center protein that can efficiently convert solar energy into fuel. The protein showed high stability, modular structure, and nanometer-scale photochemical charge separation, making it ideal for light-activated catalysis. This study demonstrates the potential of synthetic biology in creating genetically encoded, light-powered catalysts for solar fuel production.
NATURE COMMUNICATIONS
(2022)
Editorial Material
Multidisciplinary Sciences
Stefan G. Krimmer, Joseph Schlessinger
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Multidisciplinary Sciences
Iris K. van Alderwerelt van Rosenburgh, David M. Lu, Michael J. Grant, Steven E. Stayrook, Manali Phadke, Zenta Walther, Sarah B. Goldberg, Katerina Politi, Mark A. Lemmon, Kumar D. Ashtekar, Yuko Tsutsui
Summary: This study investigates the molecular basis for the varying response of non-small cell lung cancers driven by EGFR mutations to tyrosine kinase inhibitors. The researchers identify structural features that contribute to inhibitor sensitivity and propose a classification system for predicting clinical outcomes.
NATURE COMMUNICATIONS
(2022)
Article
Multidisciplinary Sciences
Stefan G. Krimmer, Nicole Bertoletti, Yoshihisa Suzuki, Luka Katic, Jyotidarsini Mohanty, Sheng Shu, Sangwon Lee, Irit Lax, Wei Mi, Joseph Schlessinger
Summary: The development of various cells, including hematopoietic stem cells and germ cells, relies on the receptor tyrosine kinase KIT and its ligand stem cell factor (SCF). Somatic mutations in KIT lead to several types of human cancers. Cryo electron microscopy analysis reveals that oncogenic KIT mutants exhibit distinct structural arrangements compared to wild-type KIT. The D5 region of KIT is identified as a potential target for therapeutic intervention.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
Letter
Urology & Nephrology
Dennis G. Moledina, Olivia Belliveau, Yu Yamamoto, Tanima Arora, Kyle A. Carey, Matthew Churpek, Melissa Martin, Caitlin M. Partridge, Sherry G. Mansour, Chirag R. Parikh, Jay L. Koyner, F. Perry Wilson
AMERICAN JOURNAL OF KIDNEY DISEASES
(2021)