Spatial aspects of oncogenic signalling determine the response to combination therapy in slice explants from Kras‐driven lung tumours |
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| Authors: | Katja Närhi Ashwini S Nagaraj Elina Parri Riku Turkki Petra W van Duijn Annabrita Hemmes Jenni Lahtela Virva Uotinen Mikko I Mäyränpää Kaisa Salmenkivi Jari Räsänen Nina Linder Jan Trapman Antti Rannikko Olli Kallioniemi Taija M Af Hällström Johan Lundin Wolfgang Sommergruber Simon Anders Emmy W Verschuren |
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| Affiliation: | 1. Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland;2. Department of Urology, Josephine Nefkens Institute, Erasmus Medical Center, Rotterdam, The Netherlands;3. Department of Pathology, University of Helsinki, Helsinki, Finland;4. HUSLAB, Division of Pathology, Helsinki University Hospital, Helsinki, Finland;5. Heart and Lung Centre, Department of General Thoracic and Oesophageal Surgery, Helsinki University Hospital, Helsinki, Finland;6. Department of Pathology, Josephine Nefkens Institute, Erasmus Medical Centre, Rotterdam, The Netherlands;7. Department of Urology, Helsinki University Hospital, Helsinki, Finland;8. Orion Corporation, Orion Pharma, Espoo, Finland;9. Department of Lead Discovery, Boehringer Ingelheim RCV GmbH & Co. KG, Vienna, Austria;10. Centre for Molecular Biology of the University of Heidelberg (ZMBH), Heidelberg, Germany |
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| Abstract: | A key question in precision medicine is how functional heterogeneity in solid tumours informs therapeutic sensitivity. We demonstrate that spatial characteristics of oncogenic signalling and therapy response can be modelled in precision‐cut slices from Kras‐driven non‐small‐cell lung cancer with varying histopathologies. Unexpectedly, profiling of in situ tumours demonstrated that signalling stratifies mostly according to histopathology, showing enhanced AKT and SRC activity in adenosquamous carcinoma, and mitogen‐activated protein kinase (MAPK) activity in adenocarcinoma. In addition, high intertumour and intratumour variability was detected, particularly of MAPK and mammalian target of rapamycin (mTOR) complex 1 activity. Using short‐term treatment of slice explants, we showed that cytotoxic responses to combination MAPK and phosphoinositide 3‐kinase–mTOR inhibition correlate with the spatially defined activities of both pathways. Thus, whereas genetic drivers determine histopathology spectra, histopathology‐associated and spatially variable signalling activities determine drug sensitivity. Our study is in support of spatial aspects of signalling heterogeneity being considered in clinical diagnostic settings, particularly to guide the selection of drug combinations. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland. |
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| Keywords: | non‐small‐cell lung cancer prostate cancer oncogenic signalling precision‐cut slices targeted therapy spatial heterogeneity |
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