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The allele-specific lipid sensing of KRAS mutants
A hallmark of RAS pathophysiology is the compartmentalization of their oncogenic signaling to the proteolipid nanoclusters on the plasma membrane (PM). This suggests that RAS oncogenesis requires a unique local PM lipid environment. Significant efforts over the past several decades have revealed an intricate selectivity of RAS proteins for distinct lipids. The enrichment of distinct lipids within RAS nanoclusters is pathologically important because RAS effectors possess their own lipid-binding/recognition motifs. Membrane binding, activation and signal transmission of these effectors require synergistic binding to both mutant RAS and specific lipids in the PM. This remarkable lipid specificity points to the possibility of targeting lipid metabolism as a viable strategy to inhibit RAS oncogenesis. The selective lipid sensing function of the RAS C-terminal membrane-anchoring domains has been the primary focus of research efforts. For instance, with respect to HRAS, NRAS, and KRAS4A, combinations of their palmitoyl and farnesyl chains contribute to their POSTED: 7/8/2025
Therapeutic strategies to overcome KRAS (OFF) inhibitors resistance
In the realm of driver oncogenes, KRAS has historically been considered ‘undruggable’ due to a lack of actionable binding sites within the mutant isoforms. Nevertheless, crucial advancements in drug design have recently led to the generation and clinical use of inhibitors that specifically target mutant KRAS in its inactive form ¬–KRAS(OFF) inhibitors sotorasib and adagrasib (1,2). However, the initial enthusiasm towards these new drugs rapidly diminished upon evidence of fast-emerging clinical resistance that highlighted the limitations of these therapies (3,4). While primary and acquired resistance have been identified, the full spectrum of mutations that drive tumor resistance remains largely unexplored, and the heterogeneity observed in patients suggests that we have just reached the tip of the iceberg. Additionally, non-genetic factors may explain the relapse in patients without detectable mutations. Preclinical studies had predicted that reactivation of MAPK signaling, marked by increased KRAS G12C-GTP loading or activation of wild-type RAS (KRAS POSTED: 9/26/2024
MAP2K4: New kid on the MAP Kinase block
Robin A Jansen is a post-doctoral fellow at the lab of Rene Bernards at the Netherlands Cancer Institute in Amsterdam. Her research focuses on finding effective drug combinations in the MAP kinase pathway. Rene Bernards is a senior staff scientist at the Netherlands Cancer Institute. His laboratory focuses on finding highly effective drug combinations for cancer. The concept of targeted therapy in the fight against cancer was first proposed by German Nobel laureate Paul Ehrlich in the 1890s, long before the identification of the first cancer-causing oncogenes. Ehrlich described this concept as ‘magic bullets’ that would be completely specific for the target and therefore safe without any additional toxicity to the body 1. However, for decades, due to lack of knowledge regarding the biological hallmarks of cancer, anticancer drugs were limited to cytotoxic chemotherapeutic agents that would affect not only the tumor cells but also healthy tissue, causing extensive toxicity POSTED: 6/18/2024
AI-generated protein biosensors enable quantitative measurements of endogenous RAS activity in live cells
Jason Z Zhang is a Helen Hay Whitney HHMI postdoctoral fellow in the lab of David Baker at University of Washington. His research is focused on AI-based de novo protein design to understand signal transduction. Measuring the levels of active Ras in living cells poses a formidable challenge due to their low abundance in cells and the dynamic nature of Ras signaling. Ras undergoes rapid cycling between active (GTP-bound) and inactive (GDP-bound) states, demanding techniques that capture these swift transitions. Traditional biochemical assays often involve cell lysis, and lack the ability to perform “in cell biochemistry” where the spatial and temporal nuances of Ras are captured within intact cells. Additionally, the sheer diversity of Ras isoforms further complicates measurements, as each isoform exhibits distinct regulatory mechanisms. Advanced imaging techniques, such as fluorescence resonance energy transfer (FRET), or bioluminescence resonance energy transfer (BRET), offer glimpses into Ras dynamics within live cells POSTED: 4/30/2024
Top-Down Proteomics Reveals the KRAS Proteoform Landscape in Colorectal Cancer
Lauren Adams is currently a senior Ph.D. candidate in Neil Kelleher’s laboratory at Northwestern University. She combines the precision of top-down mass spectrometry with molecular biology techniques to identify, characterize, and probe the functionality of KRAS proteoforms in cancer. Neil Kelleher is a professor at Northwestern University who has devoted his career to developing top-down mass spectrometry techniques and applying them to better understand proteoform-level biology. Caroline DeHart leads the mass spectrometry team for the NCI RAS Initiative at the Frederick National Laboratory for Cancer Research in Frederick, MD. She employs targeted top-down proteomics to study RAS proteoforms in various cancer contexts and applies complementary proteomic methods to elucidate the roles of post-translational modifications in oncogenic signaling pathways. Proteomics is a broad term that can generically be defined as the study of the proteome, or the landscape of proteins expressed within a given biological context. More specifically, proteomics can entail POSTED: 3/24/2024
Development of Mutant KRAS Molecuar Target Drugs and Future Prospects: Report
Fuyuhiko Tamanoi is a professor at Kyoto University and also holds a cross-appointment at UCLA where he studies signal transduction and cancer therapy. He has recently been involved in initiating new approaches to radiation therapy at Kyoto University. He completed his PhD at Nagoya University and postdoctoral research at Harvard Medical School. Before his professorship at UCLA, he worked as a senior staff investigator at Cold Spring Harbor Laboratory and then as an assistant/associate professor at the University of Chicago. Hideyuki Saya received his MD from Kobe University School of Medicine and completed his residency in neurosurgery before conducting his PhD research at the Graduate School of Medical Sciences. He completed his postdoctoral fellowship at UCSF, after which he became an assistant professor of Neuro-oncology at the MD Anderson Cancer Center. He served as a Professor at Kumamoto University School of Medicine, and subsequently, he held a professorial position at POSTED: 2/29/2024
Senescent macrophages promote oncogenic KRAS-driven lung cancer and suppress anti-tumour immunity
Dr Scott Haston obtained a BSc in Anatomical Sciences (University of Dundee, Scotland) in 2013 and a PhD in Genetics and Cell Biology (University College London) in 2019. Scott is currently a senior Postdoctoral Research Fellow in the laboratory of Professor Juan Pedro-Martinez-Barbera at University College London's Institute of Child Health. With 10 years of experience in genetics, cell biology and genetically engineered mouse models, Scott's research delves into the connections between cellular senescence, tumorigenesis, and biological aging. Specifically, Scott investigates whether cellular senescence and its associated pro-inflammatory signalling dynamics promote tumour formation and whether this is therapeutically targetable to prevent tumourigenesis or restrict tumour growth, improving ageing outcomes. His PhD research unveiled an important role for cellular senescence in driving paediatric pituitary tumourigenesis non-cell autonomously. Following this, in his postdoctoral career, he continues to make use of novel genetically engineered mouse models, revealing new insights into the influence of POSTED: 2/5/2024
Inhibition of the MAPK pathway induces re-localization of membranous proteins, leading to adaptive resistance to KRAS G12C inhibitor mediated by YAP-induced MRAS
Yuta Adachi is a staff scientist in the laboratory of Hiromichi Ebi at the Aichi Cancer Center Research Institute in Nagoya, Japan. His research is focused on interrogating mechanisms by which KRAS mutant tumor cells escape from mutant specific KRAS inhibitors. Hiromichi Ebi is Chief of the Division of Molecular Therapeutics at the Aichi Cancer Center Research Institute and Director of the Precision Medicine Center at Aichi Cancer Center Hospital. He is also Adjunct Professor of the Division of Advanced Cancer Therapeutics at the Nagoya University Graduate School of Medicine. In his post-doctoral work, Dr. Ebi studied strategies to improve the efficacy of molecular targeting agents in the laboratory of Dr. Jeffrey Engelman at the Massachusetts General Hospital Cancer Center. The recent development of KRAS G12C inhibitors has led to a paradigm shift in the treatment of these RAS mutant cancers. However, the rapid development of drug resistance suggests that POSTED: 11/1/2023
New type of bifunctional molecules perturb K-Ras interactions with membranes
Johannes Morstein is an NCI K99/R00 Postdoctoral Fellow in the group of Dr. Shokat. He is working on expanding the druggability of GTPases and protein-membrane interfaces. Kevan Shokat is a professor at the University of California at San Francisco and leader in the search for novel targeted therapeutics. He successfully developed the first covalent inhibitor of mutant KRAS (Sotorasib), which saw FDA approval in 2021 for the treatment of adults with non-small cell lung cancer (NSCLC) that carry the KRAS G12C mutation. Most drug molecules currently are monofunctional. This means that they bind to a single biological target, which can be a receptor, transporter, or enzyme (all different types of proteins). However, in recent years several research groups have succeeded in developing bifunctional molecules, which simultaneously bind to two different biological targets. There are many clever ways this technology can be used. For example, it can bring a specific disease-causing POSTED: 9/28/2023