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
Biochemistry & Molecular Biology
Daniel A. Bonsor, Dhirendra K. Simanshu
Summary: RAF activation is a crucial step for signal transduction in the MAPK pathway. The SHOC2-MRAS-PP1C (SMP) holoenzyme complex, consisting of SHOC2, MRAS, and PP1C, plays a key role in activating RAF kinases. Recent research has provided valuable insights into the structure and function of the SMP complex, including its assembly, the impact of the nucleotide state of MRAS, and the involvement of SHOC2 and MRAS in PP1C activity and specificity. Understanding the SMP complex could lead to potential therapeutic strategies for RAS/RAF-driven cancers and RASopathies.
Article
Oncology
Oren Yakovian, Julia Sajman, Rand Arafeh, Yair Neve-Oz, Michal Alon, Yardena Samuels, Eilon Sherman
Summary: The study reveals the nanoscale organization and signal coupling of NRas and BRAF in melanoma cells, showing that mutant NRas exhibits more pronounced self-clustering and increased association with BRAF. The findings suggest a new regulatory mechanism for NRas signaling and potential therapeutic targets for MEK inhibitors in melanoma.
Article
Chemistry, Medicinal
Peng Zhao, Linghang Zhuang, Xiangzhu Wang, Song Huang, Heping Wu, Yu Zhou, Yuna Yan, Fan Zhang, Ru Shen, Jing Li, Suxing Liu, Rumin Zhang, Ping Dong, Yuchang Mao, Yuanmin Fan, Chunyong He, Jiakang Sun, Lei Zhang, Qiyue Hu, Hong Wan, Jun Feng, Chang Bai, Feng He, Weikang Tao
Summary: A molecule called SHR902275 (or molecule 33) has been discovered with significantly improved potency and solubility, which shows potential for targeting cancers with mutant RAS and wild type RAF activity. In vivo experiments have demonstrated dose dependent efficacy of molecule 33.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Oncology
Shumei Kato, Robert Porter, Ryosuke Okamura, Suzanna Lee, Ori Zelichov, Gabi Tarcic, Michael Vidne, Razelle Kurzrock
Summary: The study found that patients with tumors harboring RAS alterations with high MAPK activity had significantly longer median progression-free survival (PFS) and overall survival when treated with MEK inhibitors. This correlation between RAS-mutant cancers with greater MAPK signaling and PFS suggests potential clinical benefit of MEK inhibitor treatment.
EUROPEAN JOURNAL OF CANCER
(2021)
Review
Immunology
Xuan Wu, Wenping Song, Cheng Cheng, Ziyang Liu, Xiang Li, Yu Cui, Yao Gao, Ding Li
Summary: Three isoforms of RAS gene, KRAS, NRAS, and HRAS, are the most mutated family of small GTPases in cancer. While targeted immunotherapies have improved the survival of patients with non-KRAS-mutant cancer, RAS-mutant cancers still have a poor prognosis due to their high aggressiveness. However, recent advances in the use of allele-specific covalent inhibitors have led to the development of effective pharmacological interventions against RAS-mutant cancer, such as Sotorasib (AMG510) for KRAS-G12C mutant NSCLC. This review summarizes the progress and promise of small-molecule inhibitors in clinical trials to improve the prognosis of tumors with RAS mutations.
FRONTIERS IN IMMUNOLOGY
(2023)
Article
Oncology
Jiawan Wang, Kai Pollard, Ana Calizo, Christine A. Pratilas
Summary: The study demonstrates that the combination of MEK and MET inhibitors may delay or prevent acquired resistance to MEK inhibitors through a novel mechanism, with clinical implications for MPNST patients with NF1 alterations.
Article
Oncology
Wenwen Geng, Meiling Cao, Ke Dong, Junhua An, Haidong Gao
Summary: Our study revealed that aberrant activation of the mTOR pathway is a characteristic alteration in triple-negative breast cancer (TNBC), but the mTOR pathway inhibitor everolimus is not effective for TNBC patients. We identified that the activation of the ERK pathway is an important mechanism of resistance to everolimus in TNBC cells, and SHOC2 plays a critical role in mediating this pathway. Knockdown of SHOC2 significantly inhibited the activation of the Raf-ERK pathway induced by everolimus. Moreover, interference with SHOC2 expression in combination with everolimus had significant effects on cell cycle progression and apoptosis in vitro experiments.
CANCER BIOLOGY & THERAPY
(2023)
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
Chemistry, Multidisciplinary
Charles W. Morgan, Ian L. Dale, Andrew P. Thomas, James Hunt, Jason W. Chin
Summary: In this study, bio-orthogonal ligand tethering (BOLT) was used to selectively target inhibitors to CRAF, showing that selective CRAF inhibition promotes paradoxical activation. This suggests that BOLT may be used to triage potential targets for drug discovery before any target-selective small molecules are known.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2021)
Article
Oncology
Bob Meeusen, Emanuela Elsa Cortesi, Judit Domenech Omella, Anna Sablina, Juan-Jose Ventura, Veerle Janssens
Summary: This study found that the loss of PP2A activator PTPA in KRAS-mutant lung adenocarcinomas is associated with poorer overall survival, increased cell growth, and accelerated tumor formation. Additionally, the depletion of PPP2R4 induced resistance against MEK inhibitor but sensitized cells to mTOR inhibitor, highlighting its clinical relevance in NSCLC etiology and kinase inhibitor response.
Article
Biochemistry & Molecular Biology
Trinity Cookis, Carla Mattos
Summary: The interaction between Ras and Raf-kinase through the Raf's Ras-binding and CRD domains is crucial for signal transduction. The Ras dimer model formed through the alpha 4-alpha 5 interface plays a key role in regulating the function of Ras and Raf.
Article
Oncology
Marta Llaurado Fernandez, E. Marielle Hijmans, Annemiek M. C. Gennissen, Nelson K. Y. Wong, Shang Li, G. Bea A. Wisman, Aleksandra Hamilton, Joshua Hoenisch, Amy Dawson, Cheng -Han Lee, Madison Bittner, Hannah Kim, Gabriel E. DiMattia, Christianne A. R. Lok, Cor Lieftink, Roderick L. Beijersbergen, Steven de Jong, Mark S. Carey, Rene Bernards, Katrien Berns
Summary: In Low-grade serous ovarian cancer (LGSOC), targeting specific genes can reverse resistance to MEKi. Combining pan-RAF inhibitors with MEKi shows promise in treating LGSOC and reduces proliferation of resistant cells.
MOLECULAR CANCER THERAPEUTICS
(2022)
Article
Pharmacology & Pharmacy
Yahong Liu, Ying Cheng, Gongchao Huang, Xiangying Xia, Xingkai Wang, Hongqi Tian
Summary: Tunlametinib is a novel MEK inhibitor with higher selectivity and anti-proliferation activity compared to current MEK inhibitors. It exhibits significant tumor suppression and cell cycle regulation in vivo. Furthermore, combination therapy of tunlametinib with other inhibitors or chemotherapeutic agents enhances the treatment response.
FRONTIERS IN PHARMACOLOGY
(2023)
Article
Oncology
Clare F. Malone, Minjee Kim, Gabriela Alexe, Kathleen Engel, Alexandra B. Forman, Amanda Robichaud, Amy Saur Conway, Amy Goodale, Ashleigh Meyer, Delan Khalid, Allen Thayakumar, John M. Hatcher, Nathanael S. Gray, Federica Piccioni, Kimberly Stegmaier
Summary: Rare but frequent in relapsed neuroblastoma, mutations that activate the RAS/MAPK signaling pathway can be effectively targeted with combination therapy of MEK inhibitors and CDK8 inhibitors. Loss of CCNC or CDK8 sensitizes neuroblastoma to MEK inhibition, and small-molecule kinase inhibitors of CDK8 enhance the response to MEK inhibitors. This research introduces a potential therapeutic combination for RAS-mutant neuroblastoma.
Editorial Material
Health Care Sciences & Services
Claire Frauenfelder, Andrew Hall, Bill Walsh, Alasdair Ross, Emma Broughton, Robert E. Hynds, Reema Nandi, Christopher O'Callaghan, Colin R. Butler
Summary: This article introduces a methodology to demonstrate aerosol dispersion in the operating room environment using simulation resources. It includes a supporting video to help operating room teams understand the importance of aerosol exposure and personal protective equipment.
SIMULATION IN HEALTHCARE-JOURNAL OF THE SOCIETY FOR SIMULATION IN HEALTHCARE
(2022)
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
Physiology
Laertis Ikonomou, Mattias Magnusson, Ruben Dries, Erica L. Herzog, Robert E. Hynds, Zea Borok, Jin-Ah Park, Steven Skolasinski, Janette K. Burgess, Leigh Turner, Sarah M. Mojarad, John E. Mahoney, Thomas Lynch, Mareike Lehmann, Victor J. Thannickal, Jamie L. Hook, Andrew E. Vaughan, Evan T. Hoffman, Daniel J. Weiss, Amy L. Ryan
Summary: The 9th biennial conference focused on the application of stem cells, cell therapies, and bioengineering in lung biology and diseases. The virtual event provided a platform for researchers to discuss advancements in the field, including technological innovations, stem cell signaling, airway engineering, viral infection response, and ethical considerations in cell-based treatments for lung diseases.
AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY
(2022)
Article
Oncology
Jesse Boumelha, Sophie de Carne Trecesson, Emily K. Law, Pablo Romero-Clavijo, Matthew A. Coelho, Kevin W. Ng, Edurne Mugarza, Christopher Moore, Sareena Rana, Deborah R. Caswell, Miguel Murillo, David C. Hancock, Prokopios P. Argyris, William L. Brown, Cameron Durfee, Lindsay K. Larson, Rachel Vogel, Alejandro Suarez-Bonnet, Simon L. Priestnall, Philip East, Sarah J. Ross, George Kassiotis, Miriam Molina-Arcas, Charles Swanton, Reuben Harris, Julian Downward
Summary: This study develops a mouse model of immunogenic KRAS-mutant lung cancer to facilitate the investigation of optimal combinations of targeted therapies with immunotherapies.
Article
Cell Biology
Katie L. Dale, Jonathan W. Armond, Robert E. Hynds, Elina Vladimirou
Summary: The study developed a high-throughput, single-cell, image-based method to detect chromosomal instability (CIN) and investigated the initiating conditions of CIN by activating key genes using CRISPR. The results showed that even modest changes in gene expression are sufficient to initiate CIN, exposing the fragilities of the mitotic spindle and leading to a genomically diverse cell population.
JOURNAL OF CELL SCIENCE
(2022)
Editorial Material
Medicine, General & Internal
Miriam Molina-Arcas, Julian Downward
NEW ENGLAND JOURNAL OF MEDICINE
(2022)
Article
Multidisciplinary Sciences
Edurne Mugarza, Febe van Maldegem, Jesse Boumelha, Christopher Moore, Sareena Rana, Miriam Llorian Sopena, Philip East, Rachel Ambler, Panayiotis Anastasiou, Pablo Romero-Clavijo, Karishma Valand, Megan Cole, Miriam Molina-Arcas, Julian Downward
Summary: Recently developed KRAS(G12C) inhibitory drugs benefit lung cancer patients with KRAS(G12C) mutations, but drug resistance is common. These drugs indirectly affect antitumor immunity by reversing immunosuppression caused by oncogenic KRAS. However, the combination of KRAS(G12C) inhibitors with immune checkpoint blockade only provides synergistic benefit in highly immunogenic tumor models.
Article
Multidisciplinary Sciences
Philip East, Gavin P. Kelly, Dhruva Biswas, Michaela Marani, David C. Hancock, Todd Creasy, Kris Sachsenmeier, Charles Swanton, Julian Downward, Sophie de Carne Trecesson
Summary: The study found that 84% of patients with lung adenocarcinoma have oncogenic activation of the RAS signaling pathway, with a high proportion of activation even in KRAS wild-type tumors; patient groups with high RAS activity show adverse clinical outcomes and reduced response to chemotherapy. Stratifying patients based on oncogenic RAS transcriptional activity may ultimately assist in clinical decision-making.
NATURE COMMUNICATIONS
(2022)
Review
Biology
Robert E. Hynds
Summary: Acute and chronic lung diseases are leading causes of morbidity and mortality globally. New therapies are needed to promote the regeneration of functional lung tissue.
Article
Multidisciplinary Sciences
Elizabeth F. Maughan, Robert E. Hynds, Adam Pennycuick, Ersilia Nigro, Kate H. C. Gowers, Celine Denais, Sandra Gomez-Lopez, Kyren A. Lazarus, Jessica C. Orr, David R. Pearce, Sarah E. Clarke, Dani Do Hyang Lee, Maximillian N. J. Woodall, Tereza Masonou, Katie-Marie Case, Vitor H. Teixeira, Benjamin E. Hartley, Richard J. Hewitt, Chadwan Al Yaghchi, Gurpreet S. Sandhu, Martin A. Birchall, Christopher O'Callaghan, Claire M. Smith, Paolo De Coppi, Colin R. Butler, Sam M. Janes
Summary: This study found cell-intrinsic differences between airway epithelial cells from children and adults in both homeostatic and proliferative states, with pediatric cells showing higher colony formation ability and outcompeting adult cells in cell culture.
Article
Biochemical Research Methods
May Zaw Thin, Christopher Moore, Thomas Snoeks, Tammy Kalber, Julian Downward, Axel Behrens
Summary: In this paper, a method of lung nodule image acquisition and analysis using a micro-computed tomography scanner is introduced for translational research in lung cancer that closely mimics clinical environments. The method has the advantages of low radiation dose, high resolution, and high-throughput imaging, and utilizes specific image analysis tools for identifying different types of lung tumors.
Article
Multidisciplinary Sciences
Mohamed Ismail, Stephen R. Martin, Roger George, Francesca Houghton, Geoff Kelly, Raphael A. G. Chaleil, Panayiotis Anastasiou, Xinyue Wang, Nicola O'Reilly, Stefania Federico, Dhira Joshi, Hemavathi Nagaraj, Rachel Cooley, Ning Sze Hui, Miriam Molina-Arcas, David C. Hancock, Ali Tavassoli, Julian Downward
Summary: A cyclic peptide inhibitor (cyclo-CRVLIR) was discovered that interacts with the p110 alpha-RBD and blocks its interaction with KRAS. This inhibitor effectively blocks the p110 alpha/KRAS interaction and reduces phospho-AKT levels in several oncogenic KRAS cell lines.
SCIENTIFIC REPORTS
(2023)
Article
Multidisciplinary Sciences
Kevin Ng, Jesse Boumelha, Katey S. S. Enfield, Jorge L. Almagro, Hongui M. Cha, Oriol Pich, Takahiro Karasaki, David Moore, Roberto Salgado, Monica Sivakumar, George Young, Miriam L. Molina-Arcas, Sophie de Carne Trecesson, Panayiotis Anastasiou, Annika C. Fendler, Lewis Au, Scott T. C. Shepherd, Carlos Martinez-Ruiz, Clare Puttick, James R. M. Black, Thomas B. K. Watkins, Hyemin Kim, Seohee Shim, Nikhil Faulkner, Jan A. Attig, Selvaraju Veeriah, Neil J. Magno, Sophia T. Ward, Alexander Frankell, Maise Al Bakir, Emilia Lim, Mark Hill, Gareth Wilson, Daniel Cook, Nicolai Birkbak, Axel Behrens, Nadia Yousaf, Sanjay Popat, Allan Hackshaw, TRACERx Consortium, CAPTURE Consortium, Crispin T. Hiley, Kevin Litchfield, Nicholas McGranahan, Mariam Jamal-Hanjani, James Larkin, Se-Hoon Lee, Samra Turajlic, Charles Swanton, Julian Downward, George Kassiotis
Summary: This study reveals that lung adenocarcinomas in both humans and mice elicit local germinal center responses and tumour-binding antibodies, with endogenous retrovirus (ERV) envelope glycoproteins as the dominant anti-tumour antibody target. ERV-targeting B cell responses are enhanced by immune checkpoint blockade (ICB) and targeted inhibition of KRAS(G12C). ERV-reactive antibodies have anti-tumour activity and improve survival in a mouse model, and ERV expression predicts the response to ICB in human lung adenocarcinoma. Furthermore, the study demonstrates that effective immunotherapy in the mouse model requires CXCL13-dependent tertiary lymphoid structure (TLS) formation, and therapeutic CXCL13 treatment enhances anti-tumour immunity and synergizes with ICB. These findings provide a potential mechanistic basis for the association between TLS and immunotherapy response.
Article
Multidisciplinary Sciences
Rowan Howell, James Davies, Matthew A. Clarke, Anna Appios, Yashoda Jayal, Ben Ringham-Terry, Isabel Boned Del Rio, Jasmin Fisher, Clare L. Bennett
Summary: Researchers have developed an in silico model to investigate the interaction between melanomas and Langerhans cells (LCs). The model suggests that melanomas do not activate LC migration to lymph nodes until they reach a critical size, due to a positive TNF-alpha feedback loop. Experimental testing confirms that treating primary tumors with MAPK pathway inhibitors can prevent LC migration. The study also predicts treatment combinations that can bypass LC dysfunction.
