Review
Biochemistry & Molecular Biology
Thomas Jung, Maximilian Haist, Michael Kuske, Stephan Grabbe, Matthias Bros
Summary: The advent of MAPK inhibitors and ICI has greatly improved the treatment of metastatic melanoma, with BRAF/MEK inhibitors used for BRAF mutation patients, showing immunomodulatory functions in addition to their antiproliferative effects.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Biochemistry & Molecular Biology
Miguel A. Zaballos, Adrian Acuna-Ruiz, Marta Morante, Garcilaso Riesco-Eizaguirre, Piero Crespo, Pilar Santisteban
Summary: The study demonstrates that BRAF- and RAS-mutant thyroid cells respond differently to DEL-22379, which cannot be explained by the previously described mechanism of action of the inhibitor. Nonetheless, DEL-22379 exhibits significant anti-tumor effects against BRAF-mutant cells in vivo, while the anti-tumor effects are mild for RAS-mutant cells.
CELLULAR AND MOLECULAR LIFE SCIENCES
(2022)
Article
Oncology
Mattia Garutti, Melissa Bergnach, Jerry Polesel, Lorenza Palmero, Maria Antonietta Pizzichetta, Fabio Puglisi
Summary: To date, the combination of BRAF and MEK inhibitors is commonly used for the treatment of mutated BRAF metastatic melanoma. However, there is no evidence to support the superiority of one combination over others, and safety data is limited. In this meta-analysis, we evaluated the adverse events associated with each treatment combination to provide clinicians with information for tailored patient treatment.
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.
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
Oncology
Pui-Kei Wu, Seung-Keun Hong, Jong-In Park
Summary: The study found that RNA interference of mortalin can induce cell death in vemurafenib-resistant B-Raf mutant melanoma cells, and chemical inhibition of MEK1/2 and ERK1/2 can suppress mortalin depletion-induced death. Therefore, mortalin may serve as a potential therapeutic target for BRAFi-resistant BRAF mutant tumors.
Article
Oncology
Avirup Guha, Prantesh Jain, Michael G. Fradley, Daniel Lenihan, Jahir M. Gutierrez, Chhavi Jain, Marcos de Lima, Jill S. Barnholtz-Sloan, Guilherme H. Oliveira, Afshin Dowlati, Sadeer Al-Kindi
Summary: In comparison to monotherapy with BRAF inhibitors, combination therapy with BRAF/MEK inhibitors is associated with increased cardiovascular adverse events (CVAEs), primarily heart failure (HF) and hypertension, as confirmed in two independent real-world cohorts.
Article
Chemistry, Medicinal
Aarion Romany, Ruibin Liu, Shaoqi Zhan, Joseph Clayton, Jana Shen
Summary: The ERK pathway is crucial in tumorigenesis and there is a need for novel covalent inhibitors due to limited efficacy of current noncovalent inhibitors approved by FDA. A systematic study revealed possible targets for the development of covalent inhibitors against ERK pathway kinases.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2023)
Review
Oncology
Thomas Yul Avery, Natalie Koehler, Robert Zeiser, Tilman Brummer, Dietrich Alexander Ruess
Summary: Hyperactivation of the RAS-RAF-MEK-ERK cascade plays a significant role in the oncogenesis of various tumors. It mediates the crosstalk between tumor, tumor microenvironment, and the immune system, leading to immune escape mechanisms and establishment of a tumor-supporting environment. Pharmacological interruption of this pathway disrupts tumor cells and modifies the tumor microenvironment, as well as anti-tumor immunomodulation. MEK inhibition has shown promise in modulating immune responses. However, the durable efficacy, therapy resistance, and toxicity still pose challenges for the clinical application of therapeutic agents targeting RAS-RAF-MEK-ERK hyperactivation.
FRONTIERS IN ONCOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Emmanuelle M. Ruiz, Solomon A. Alhassan, Youssef Errami, Zakaria Y. Abd Elmageed, Jennifer S. Fang, Guangdi Wang, Margaret A. Brooks, Joe A. Abi-Rached, Emad Kandil, Mourad Zerfaoui
Summary: A 13-gene panel was identified to accurately predict resistance to BRAF/MEK inhibitor therapy in melanoma patients. Dysregulation of HMOX1, ICAM, MMP2, and SPARC defined a treatment-resistant landscape, and HMOX1-mediated mitochondrial stress response was identified as a potential key driver of resistance. These findings highlight the importance of these genes in predicting treatment outcomes and targeting underlying mechanisms to reduce resistance development.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Biochemistry & Molecular Biology
Peng-Chieh Chen, Ya-Wen Hsueh, Yi-Hsuan Lee, Hung-Wen Tsai, Kuen-Jer Tsai, Po-Min Chiang
Summary: To elucidate the specific role of FGF in mesoderm-to-endothelium differentiation, researchers minimized secondary artifacts by manipulating FGF and downstream mediators with short incubation times and protein-synthesis blockage. The study revealed that FGF plays a crucial role in driving the angioblastic conversion from mesoderm-to-endothelium by priming cells through the FGFR1/BRAF/MEK/ERK pathway, with ETV2 and LMO2 identified as early direct functional responders downstream of the FGF pathway.
CELLULAR AND MOLECULAR LIFE SCIENCES
(2021)
Article
Oncology
Elisa Izquierdo, Diana M. Carvalho, Alan Mackay, Sara Temelso, Jessica K. R. Boult, Giulia Pericoli, Elisabet Fernandez, Molina Das, Valeria Molinari, Yura Grabovska, Rebecca F. Rogers, Maria Antonietta Ajmone-Cat, Paula Z. Proszek, Mark Stubbs, Sarita Depani, Patricia O'Hare, Lu Yu, Georgia Roumelioti, Jyoti S. Choudhary, Matthew Clarke, Amy R. Fairchild, Thomas S. Jacques, Richard G. Grundy, Lisa Howell, Susan Picton, Jenny Adamski, Shaun Wilson, Juliet C. Gray, Bassel Zebian, Lynley Marshall, Fernando Carceller, Jacques Grill, Maria Vinci, Simon P. Robinson, Michael Hubank, Darren Hargrave, Chris Jones
Summary: The MAPK pathway is a therapeutic target in DIPG, and combination therapy with trametinib and dasatinib may overcome single-agent resistance.
Article
Oncology
Hui-Huang Lai, Liang-Yi Hung, Chia-Jui Yen, Hsu-Chin Hung, Ruo-Yu Chen, Yu-Chao Ku, Hang-Tat Lo, Hung-Wen Tsai, Yun-Ping Lee, Tz-Hsuan Yang, Yen-Yu Chen, Yi-Shuian Huang, Wenya Huang
Summary: The overexpression of DNA repair gene NEIL3 in hepatocellular carcinoma (HCC) is associated with tumor development and metastasis. NEIL3 activates specific pathways to promote epithelial-mesenchymal transition, leading to tumor resistance and metastasis. This study suggests that NEIL3 may serve as a potential biomarker for predicting HCC recurrence and clinical intervention.
JOURNAL OF PATHOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Anwar Shabna, Jayesh Antony, Vinod Vijayakurup, Minakshi Saikia, Vijayasteltar B. Liju, Archana P. Retnakumari, Nisthul A. Amrutha, Vijai V. Alex, Mundanattu Swetha, Sreekumar U. Aiswarya, Somaraj Jannet, Uma Subramanian Unni, Sankar Sundaram, Daisy R. Sherin, Nikhil Ponnoor Anto, Smitha Bava, Sadasivan Chittalakkottu, Sophia Ran, Ruby John Anto
Summary: This article investigates the mechanism of drug resistance in melanoma and the anti-tumor activity of tryptanthrin, a compound from Wrightia tinctoria, in melanoma. The study found that tryptanthrin inhibits melanoma invasion and metastasis by down-regulating MITF-M expression.
CELLULAR AND MOLECULAR LIFE SCIENCES
(2022)
Article
Gastroenterology & Hepatology
Gajanan Kendre, Karthikeyan Murugesan, Tilman Brummer, Oreste Segatto, Anna Saborowski, Arndt Vogel
Summary: This study retrospectively analyzed the genomic data of 6,130 patients diagnosed with intrahepatic cholangiocarcinoma (iCCA), and identified seven oncogenic driver genes and their co-mutational patterns. The study also discovered genetic variations and genomic patterns associated with iCCA, which are important for developing effective treatment strategies and predicting mechanisms of resistance.
JOURNAL OF HEPATOLOGY
(2023)
Article
Cell Biology
Lino Rohrer, Corinna Spohr, Carina Beha, Ricarda Griffin, Sandra Braun, Sebastian Halbach, Tilman Brummer
Summary: The dimerization of RAF kinases plays a crucial role in their activation and the activation of the RAS/ERK pathway. Recent studies have developed a split luciferase system to study the homo- and heterodimerization of BRAF, RAF1, and KSR1. It was found that KRAS(G12V) promotes the dimerization of BRAF, while KSR1 can form homo- and KSR1/BRAF heterodimers even in the absence of KRAS(G12V) through a salt bridge between the CC-SAM domain of KSR1 and the BRAF-specific region.
CELL COMMUNICATION AND SIGNALING
(2023)
Article
Oncology
Melanie Langhammer, Julia Schoepf, Timo Jaquet, Katharina Horn, Moritz Angel, Corinna Spohr, Daniel Christen, Franziska Maria Uhl, Tiago Maie, Henrike Jacobi, Thorsten B. Feyerabend, Julia Huber, Marcus Panning, Cassian Sitaru, Ivan Costa, Robert Zeiser, Konrad Aumann, Heiko Becker, Till Braunschweig, Steffen Koschmieder, Khalid Shoumariyeh, Michael Huber, Mirle Schemionek-Reinders, Tilman Brummer, Sebastian Halbach
Summary: The persistence of leukemic stem cells (LSCs) in chronic myeloid leukemia (CML) presents a challenge in therapy. This study investigates the role of mast cells (MCs) in CML progression and suggests targeting MCs as an additional approach for CML treatment. The BCR::ABL1 fusion gene drives the expansion of bone marrow-derived MCs and enhances their responsiveness to degranulation triggers. In CML patients, splenomegaly is associated with increased BM MC counts and elevated pro-inflammatory cytokines, indicating the importance of MCs in disease progression.
Article
Oncology
Marlene Langenbach, Sophie Giesler, Stefan Richtsfeld, Sara Costa-Pereira, Lukas Rindlisbacher, Tobias Wertheimer, Lukas M. Braun, Geoffroy Andrieux, Sandra Duquesne, Dietmar Pfeifer, Nadine M. Woessner, Hans D. Menssen, Sanaz Taromi, Justus Duyster, Melani Boerries, Tilman Brummer, Bruce R. Blazar, Susana Minguet, Patrick Turko, Mitchell P. Levesque, Burkhard Becher, Rober Zeiser
Summary: Treatment of metastatic melanoma with immune checkpoint inhibitors (ICI) has high response rates, but resistance to ICI impacts patient survival. In this study, the role of MDM2 inhibition in enhancing ICI therapy was investigated using mouse models and patient-derived melanoma cells. MDM2 inhibition induced expression of IL15 and MHC-II in melanoma cells through p53 induction. This enhanced antitumor immunity and induced anti-melanoma immune memory. In patients, increased IL15 and MHC-II expression correlated with better prognosis in WT melanoma but not TP53-mutated melanoma.
MOLECULAR CANCER RESEARCH
(2023)
Meeting Abstract
Oncology
Romain Sigaud, Anja Stefanski, Florian Selt, Thomas Hielscher, Diren Usta, Daniela Kocher, Daniel Picard, Isabel Budenbender, Marc Remke, Stefan M. Pfister, David T. W. Jones, Tilman Brummer, Olaf Witt, Till Milde
Meeting Abstract
Oncology
Romain Sigaud, Thomas K. Albert, Caroline Hess, Thomas Hielscher, Nadine Winkler, Carolin Walter, Daniel Muenter, Florian Selt, Diren Usta, Jonas Ecker, Angela Brentrup, Martin Hasselblatt, Christian Thomas, Julian Varghese, David Capper, Ulrich W. Thomale, Pablo Hernaiz Driever, Michele Simon, Svea Horn, Nina Annika Herz, Arend Koch, Felix Sahm, Stefan Hamel Mann, Augusto Faria Andrade, Nada Jabado, Antoinette Y. N. Schouten-van Meeteren, Eelco Hoving, Tilman Brummer, Cornelis M. van Tilburg, Stefan M. Pfister, Olaf Witt, David T. W. Jones, Kornelius Kerl, Till Milde
Article
Biochemistry & Molecular Biology
Danda Chapagai, George Merhej, Campbell McInnes, Michael D. Wyatt
Summary: Polo-like kinase 1 (PLK1) is a crucial protein kinase involved in multiple mitotic processes, and its regulation is mediated by the interaction between its kinase domain (KD) and phosphopeptide-binding polobox domain (PBD). This study compared the activity of PBD-binding molecules (abbapolins) with KD inhibitors to understand the conformational features of PLK1. Abbapolins were found to thermally stabilize PLK1, while KD inhibitors caused a decrease in soluble PLK1 and a less stable conformation. Binding measurements and cellular consequences also revealed distinct effects of KD versus PBD engagement, suggesting the relief of autoinhibited PLK1 by KD binders. These findings have significant implications for targeting PLK1 and the development of ATP-competitive PLK1 inhibitors.
ACS CHEMICAL BIOLOGY
(2023)
Article
Multidisciplinary Sciences
Romain Sigaud, Thomas K. Albert, Caroline Hess, Thomas Hielscher, Nadine Winkler, Daniela Kocher, Carolin Walter, Daniel Muenter, Florian Selt, Diren Usta, Jonas Ecker, Angela Brentrup, Martin Hasselblatt, Christian Thomas, Julian Varghese, David Capper, Ulrich W. Thomale, Pablo Hernaiz Driever, Michele Simon, Svea Horn, Nina Annika Herz, Arend Koch, Felix Sahm, Stefan Hamelmann, Augusto Faria-Andrade, Nada Jabado, Martin U. Schuhmann, Antoinette Y. N. Schouten-van Meeteren, Eelco Hoving, Tilman Brummer, Cornelis M. van Tilburg, Stefan M. Pfister, Olaf Witt, David T. W. Jones, Kornelius Kerl, Till Milde
Summary: The authors develop MAPKi sensitivity scores (MSS) to predict response to MAPKi in pediatric low-grade gliomas (pLGG) and validate their effectiveness using bulk and single-cell sequencing datasets. The MSSs successfully distinguish sensitive and non-sensitive cells and correlate with treatment response in independent datasets. These MSSs are important for patient stratification and should be validated in clinical trials.
NATURE COMMUNICATIONS
(2023)
Article
Multidisciplinary Sciences
Manuel Lauinger, Daniel Christen, Rhena F. U. Klar, Carole Roubaty, Christoph E. Heilig, Michael Stumpe, Jennifer J. Knox, Nikolina Radulovich, Laura Tamblyn, Irene Y. Xie, Peter Horak, Andrea Forschner, Michael Bitzer, Uwe A. Wittel, Melanie Boerries, Claudia R. Ball, Christoph Heining, Hanno Glimm, Martina Froehlich, Daniel Huebschmann, Steven Gallinger, Ralph Fritsch, Stefan Froehling, Grainne M. O'Kane, Joern Dengjel, Tilman Brummer
Summary: This study functionally characterizes BRAF exon 12 deletions and compares them with other BRAF ss 3-alpha C mutants. It demonstrates that BRAF(Delta ss 3-alpha C) deletion mutants form stable dimers and multiprotein complexes, and their dimerization is necessary. Some mutants with aromatic amino acid insertions at the deletion junction exhibit resistance to monomer-favoring RAF inhibitors while being sensitive to dimer-favoring inhibitors.
Meeting Abstract
Oncology
Corinna Spohr, Teresa Poggio, Geoffroy Andrieux, Katharina Schoenberger, Nina Cabezas-Wallscheid, Melanie Boerries, Sebastian Halbach, Anna L. Illert, Tilman Brummer
Meeting Abstract
Oncology
P. Adelberger, T. Poggio, C. Rummelt, C. Orcinha, S. Gorantla, L. Grassel, K. Stock, S. Yacob, C. Endres, M. Hess, J. Duyster, M. Borries, T. Brummer, A. - L. Illert
ONCOLOGY RESEARCH AND TREATMENT
(2022)
Meeting Abstract
Oncology
Romain Sigaud, Caroline Hess, Thomas Hielscher, Nadine Winkler, Florian Selt, Daniela Kocher, Leo Nonnenbroich, Diren Usta, Alex Sommerkamp, Isabel Buedenbender, David Capper, Ulrich W. Thomale, Pablo Hernaiz Driever, Michele Simon, Arend Koch, Nada Jabado, Augusto F. Andrade, Netteke Schouten-van Meeteren, Eelco Hoving, Cornelis M. van Tilburg, Stefan M. Pfister, Olaf Witt, David T. W. Jones, Till Milde
Meeting Abstract
Oncology
Romain Sigaud, Lisa Roesch, Charlotte Gatzweiler, Julia Benzel, Laura von Soosten, Heike Peterziel, Sara Najafi, Simay Ayhan, Xena F. Gerloff, Nina Hofmann, Isabel Buedenbender, Kathrin I. Foerster, Juergen Burhenne, Remi Longuespee, Cornelis M. van Tilburg, David T. W. Jones, Stefan M. Pfister, Deborah Knoerzer, Brent Kreider, Max Sauter, Kristian W. Pajtler, Marc Zuckermann, Ina Oehme, Olaf Witt, Till Milde
Meeting Abstract
Oncology
Romain Sigaud, Anja Stefanski, Florian Selt, Thomas Hielscher, Diren Usta, Daniela Kocher, Daniel Picard, Isabel Buedenbender, Marc Remke, Stefan M. Pfister, David T. W. Jones, Tilman Brummer, Olaf Witt, Till Milde
Meeting Abstract
Oncology
Daniela Kocher, Florian Selt, Gintvile Valinciute, Julia Zaman, David Vonhoeren, Stefan Pusch, Romain Guiho, Juan Pedro Martinez-Barbera, Andreas von Deimling, Stefan M. Pfister, David T. W. Jones, Tilman Brummer, Olaf Witt, Till Milde, Romain Sigaud