Protein kinases function as pivotal regulators in biological events, governing essential cellular processes through the transfer of phosphate groups from ATP molecules to substrates. Dysregulation of kinase activity is frequently associated with cancer, ocasionally arising from chromosomal translocation events that relocate genes encoding kinases. Fusion proteins resulting from such events, particularly those involving the proto-oncogene tyrosine-protein kinase ROS (ROS1), manifest as constitutively active kinases, emphasizing their role in oncogenesis. Notably, the chromosomal reallocation of the ros1 gene leads to fusion of proteins with the ROS1 kinase domain, implicated in various cancer types. Despite their prevalence, targeted inhibition of these fusion proteins relies on repurposed kinase inhibitors. This review comprehensively surveys experimentally determined ROS1 structures, emphasizing the pivotal role of X-ray crystallography in providing high-quality insights. We delve into the intricate interactions between ROS1 and kinase inhibitors, shedding light on the structural basis for inhibition. Additionally, we explore point mutations identified in patients, employing molecular modeling to elucidate their structural impact on the ROS1 kinase domain. By integrating structural insights with in vitro and in silico data, this review advances our understanding of ROS1 kinase in cancer, offering potential avenues for targeted therapeutic strategies.
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In the life of flowering plants, seed germination is a critical step to ensure survival into the next generation. Generally the seed prior to germination has been in a dormant state with a low rate of metabolism. In the transition from a dormant seed to a germinating seed, various epigenetic mechanisms play a regulatory role. Here, we demonstrate that the over-expression of chromatin remodeling ATPase genes (AtCHR12 or AtCHR23) reduced the frequency of seed germination in Arabidopsis thaliana up to 30% relative to the wild-type seeds. On the other hand, single loss-of-function mutations of the two genes did not affect seed germination. The reduction of germination in over-expressing mutants was more pronounced in stress conditions (salt or high temperature), showing the impact of the environment. Reduced germinations upon over-expression coincided with increased transcript levels of seed maturation genes and with reduced degradation of their mRNAs stored in dry seeds. Our results indicate that repression of AtCHR12/23 gene expression in germinating wild-type Arabidopsis seeds is required for full germination. This establishes a functional link between chromatin modifiers and regulatory networks towards seed maturation and germination.
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Every year in the Netherlands around 10.000 people are diagnosed with non-small cell lung cancer, commonly at advanced stages. In 1 to 2% of patients, a chromosomal translocation of the ROS1 gene drives oncogenesis. Since a few years, ROS1+ cancer can be treated effectively by targeted therapy with the tyrosine kinase inhibitor (TKI) crizotinib, which binds to the ROS1 protein, impairs the kinase activity and thereby inhibits tumor growth. Despite the successful treatment with crizotinib, most patients eventually show disease progression due to development of resistance. The available TKI-drugs for ROS1+ lung cancer make it possible to sequentially change medication as the disease progresses, but this is largely a ‘trial and error’ approach. Patients and their doctors ask for better prediction which TKI will work best after resistance occurs. The ROS1 patient foundation ‘Stichting Merels Wereld’ raises awareness and brings researchers together to close the knowledge gap on ROS1-driven oncogenesis and increase the options for treatment. As ROS1+ lung cancer is rare, research into resistance mechanisms and the availability of cell line models are limited. Medical Life Sciences & Diagnostics can help to improve treatment by developing new models which mimic the situation in resistant tumor cells. In the current proposal we will develop novel TKI-resistant cell lines that allow screening for improved personalized treatment with TKIs. Knowledge of specific mutations occurring after resistance will help to predict more accurately what the next step in patient treatment could be. This project is part of a long-term collaboration between the ROS1 patient foundation ‘Stichting Merels Wereld’, the departments of Pulmonary Oncology and Pathology of the UMCG and the Institute for Life Science & Technology of the Hanzehogeschool. The company Vivomicx will join our consortium, adding expertise on drug screening in complex cell systems.
Logistics represents around 10-11% of global CO2 emissions, around 75% of which come from road freight transport. ‘The European Green Deal’ is calling for drastic CO2 reduction in this sector. This requires advanced and very expensive technological innovations; i.e. re-design of vehicle units, hybridization of powertrains and automatic vehicle technology. Another promising way to reach these environmental ambitions, without excessive technological investments, is the deployment of SUPER ECO COMBI’s (SEC). SEC is the umbrella name for multiple permutations of 32 meter, 70 tons, road-train combinations that can carry the payload-equivalent of 2 normal tractor-semitrailer combinations and even 3 rigid trucks. To fully deploy a SEC into the transport system the compliance with the existing infrastructure network and safety needs to be guaranteed; i.e. to deploy a specific SEC we should be able to determine which SEC-permutation is most optimal on specific routes with respect to regulations (a.o. damage to the pavement/bridges), the dimensions of specific infrastructures (roundabouts, slopes) and safety. The complexity of a SEC compared to a regular truck (double articulation, length) means that traditional optimisation methods are not applicable. The aim of this project is therefore to develop a first methodology enabling the deployment of the optimal SEC permutation. This will help transport companies (KIEM: Ewals) and trailer manufactures (KIEM: Emons) to invest in the most suitable designs for future SEC use. Additionally the methodology will help governments to be able to admit specific SEC’s to specific routes. The knowledge gained in this project will be combined with the knowledge of the broader project ENVELOPE (NWA-IDG). This will be the start of broader research into an overall methodology of deploying optimal vehicle combinations and a new regulatory framework. The knowledge will be used in master courses on vehicle dynamics.
How does a specific lung cancer become resistant towards medication.The occurrence of a chromosomal translocation resulting in a ROS1 gene fusion in lung cancer is relatively rare with around 1-2% of all cases. Both Dutch (Stichting Merels Wereld) and world-wide (ROS1ders) patient advocacy groups work hard to raise awareness and bring researchers together to close the knowledge gap on ROS1 driven oncogenesis and increase the optionsfor treatment. A notorious hurdle is to achieve durable responses due to development of resistance.Ongoing mutations occurring in tumour cells lead to a heterogeneous genomic landscape and will result in outgrowth of the fastest growing tumour cell population resistant to the applied drug. The currently known resistance mechanisms can be divided in on-target (i.e. mutations in the kinasedomain of ROS1) and off-target (providing ROS1 independent growth support) mechanisms. The currently available drugs target the ROS1-fusion gene positive lung cancer cells. In addition, some of the drugs also target cancer cells with specific ROS1 resistance mutations allowing effective sequentialtreatment upon disease progression. Selection of the most optimal treatment is largely a ‘trial and error’ approach. Patients and their doctors ask for better prediction of the most effective follow-up treatment upon development of resistance. Medical Life Science & Diagnostics can help to improvetreatment by developing cell culture models which mimic the situation in resistant tumour cells.Understanding the impact of specific mutations on disease behaviour will aid in the development of patient-tailored therapeutic approaches, ultimately improving patient outcomes.
