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Spatial aspects of oncogenic signalling determine the response to combination therapy in slice explants from Kras ‐driven lung tumours
Author(s) -
Närhi Katja,
Nagaraj Ashwini S,
Parri Elina,
Turkki Riku,
van Duijn Petra W,
Hemmes Annabrita,
Lahtela Jenni,
Uotinen Virva,
Mäyränpää Mikko I,
Salmenkivi Kaisa,
Räsänen Jari,
Linder Nina,
Trapman Jan,
Rannikko Antti,
Kallioniemi Olli,
Af Hällström Taija M,
Lundin Johan,
Sommergruber Wolfgang,
Anders Simon,
Verschuren Emmy W
Publication year - 2018
Publication title -
the journal of pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.964
H-Index - 184
eISSN - 1096-9896
pISSN - 0022-3417
DOI - 10.1002/path.5059
Subject(s) - kras , histopathology , pi3k/akt/mtor pathway , mapk/erk pathway , biology , cancer research , adenosquamous carcinoma , adenocarcinoma , kinase , lung cancer , targeted therapy , pathology , bioinformatics , medicine , cancer , signal transduction , microbiology and biotechnology , colorectal cancer , genetics
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.