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Mol Cancer Ther. 2019 Jul 18. pii: molcanther.0573.2018. doi: 10.1158/1535-7163.MCT-18-0573. [Epub ahead of print]

Receptor Tyrosine Kinase Signaling Networks Define Sensitivity to ERBB Inhibition and Stratify Kras Mutant Lung Cancers.

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Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki.
Division of Research, Peter MacCallum Cancer Centre.
Genome-Scale Biology Research Program, Biomedicum Helsinki, University of Helsinki.
High Throughput Biomedicine Unit, Institute for Molecular Medicine Finland.
University of Helsinki, University of Helsinki and Wihuri Research Institute.
Translational Cancer Biology Program, Research Programs Unit, University of Helsinki.
Department of Pathology, Haartman Institute and HUSLAB, University of Helsinki.
Helsinki University Hospital and University of Helsinki, HUSLAB, Division of Pathology.
BRIC - Biotech Research & Innovation Centre, University of Copenhagen.
Institute for Molecular Medicine Finland (FIMM), Institute for Molecular Medicine Finland


Most non-small cell lung cancers (NSCLCs) contain non-targetable mutations, including KRAS, TP53 or STK11/LKB1 alterations. By coupling ex vivo drug sensitivity profiling with in vivo drug response studies, we aimed to identify drug vulnerabilities for these NSCLC subtypes. Primary adenosquamous carcinoma (ASC) or adenocarcinoma (AC) cultures were established from KrasG12D;Lkb1 fl/fl (KL) tumors or AC cultures from KrasG12D;p53fl/fl (KP) tumors. While p53 null cells readily propagated as conventional cultures, Lkb1 null cells required conditional reprograming for establishment. Drug response profiling revealed short-term response to MEK inhibition, yet, long-term clonogenic assays demonstrated resistance, associated with sustained or adaptive activation of receptor tyrosine kinases (RTKs): activation of ERBBs in KL cultures, or FGFR in AC cultures. Furthermore, pan-ERBB inhibition reduced the clonogenicity of KL cultures, which was exacerbated by combinatorial MEK inhibition, while combinatorial MEK and FGFR inhibition suppressed clonogenicity of AC cultures. Importantly, in vivo studies confirmed KL-selective sensitivity to pan-ERBB inhibition, which correlated with high ERBB ligand expression and activation of ERBB receptors, implying that ERBB network activity may serve as a predictive biomarker of drug response. Interestingly, in human NSCLCs, phosphorylation of EGFR or ERBB3 was frequently detected in ASCs and squamous cell carcinomas. We conclude that analysis of in situ ERBB signaling networks in conjunction with ex vivo drug response profiling and biochemical dissection of adaptive RTK activities may serve as valid diagnostic approach to identify tumors sensitive to ERBB network inhibition.

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