Lab report on Lidar Mapping with Livox Mid-40 in ROS
MULTIFILE
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.
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.
Longtumoren waaraan een ROS1 genherschikking ten grondslag ligt worden op dit moment behandeld met ROS1-specifieke tyrosine kinase remmers (TKIs). Hoewel TKI-therapie zeer succesvol is en weinig bijwerkingen geeft ten opzichte van chemotherapie, wordt uiteindelijk in alle patiënten ziekteprogressie waargenomen door therapie-resistentie van het tumorweefsel. Moleculaire veranderingen in de tumor liggen ten grondslag aan deze resistentie. Welk effect een specifieke mutatie heeft op de gevoeligheid van de tumor voor andere TKIs is grotendeels onbekend. In dit project zullen wij ROS1-tumorcelmodellen ontwikkelen met gerichte resistentie-mutaties tegen de TKIs Lorlatinib en Repotrectinib. Deze cellijnen zullen gebruikt worden om de effectiviteit van de klinische beschikbare TKIs te bestuderen. De kennis over de gevoeligheid van cellijnen met specifieke resistentiemutaties voor de beschikbare TKIs zal de diagnostiek rondom TKI-resistentie en de gepersonaliseerde behandeling van ROS1-positieve longkankerpatiënten verbeteren. Dit project is een samenwerking tussen de Hanzehogeschool, het Universitair Medisch Centrum Groningen en de nationale en internationale patiëntenorganisaties ‘Stichting Merels Wereld’ en de ‘ROS1ders’ respectievelijk. Het project is ingebed in de onderzoekslijn Bioactivity and Health binnen het Kenniscentrum Biobased Economy en het Instituut voor Life Science & Technology van de Hanzehogeschool en past uitstekend binnen de ambities van het kenniscentrum om zich op het Thema ‘(Positive) Health’ verder te ontwikkelen.
