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

Show full item record



Permalink

http://hdl.handle.net/10138/306778

Citation

Talwelkar , S S , Nagaraj , A S , Devlin , J R , Hemmes , A , Potdar , S , Kiss , E A , Saharinen , P , Salmenkivi , K M , Mäyränpää , M I , Wennerberg , K & Verschuren , E 2019 , ' Receptor Tyrosine Kinase Signaling Networks Define Sensitivity to ERBB Inhibition and Stratify Kras Mutant Lung Cancers ' , Molecular Cancer Therapeutics , vol. 18 , no. 10 , pp. 1863-1874 . https://doi.org/10.1158/1535-7163.MCT-18-0573

Title: Receptor Tyrosine Kinase Signaling Networks Define Sensitivity to ERBB Inhibition and Stratify Kras Mutant Lung Cancers
Author: Talwelkar, Sarang S.; Nagaraj, Ashwini S.; Devlin, Jennifer R.; Hemmes, Annabrita; Potdar, Swapnil; Kiss, Elina A.; Saharinen, Pipsa; Salmenkivi, Kaisa Maria; Mäyränpää, Mikko I.; Wennerberg, Krister; Verschuren, Emmy
Contributor: University of Helsinki, Institute for Molecular Medicine Finland
University of Helsinki, Institute for Molecular Medicine Finland
University of Helsinki, Institute for Molecular Medicine Finland
University of Helsinki, Institute for Molecular Medicine Finland
University of Helsinki, Institute for Molecular Medicine Finland
University of Helsinki, CAN-PRO - Translational Cancer Medicine Program
University of Helsinki, Department of Biochemistry and Developmental Biology
University of Helsinki, HUSLAB
University of Helsinki, HUSLAB
University of Helsinki, Institute for Molecular Medicine Finland
University of Helsinki, Research Group Verschuren Emmy
Date: 2019-10
Language: eng
Number of pages: 12
Belongs to series: Molecular Cancer Therapeutics
ISSN: 1535-7163
URI: http://hdl.handle.net/10138/306778
Abstract: Most non-small cell lung cancers (NSCLC) contain nontargetable mutations, including KRAS, TP53, or STK11/LKB1 alterations. By coupling ex viva 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 Kras(G12D/+);Lkb1(fl/fl) (KL) tumors or AC cultures from Kras(G12D/+);p53(fl/fl) (KP) tumors. Although 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 (RTK): activation of ERBBs in KL cultures, or FGFR in AC niltures. Furthermore, pan-ERBB inhibition reduced the clonogenidty of KL cultures, which was exacerbated by combinatorial MEK inhibition, whereas 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 a valid diagnostic approach to identify tumors sensitive to ERBB network inhibition.
Subject: ADENOCARCINOMA
BIOLOGY
CARCINOMA
CONDITIONALLY REPROGRAMMED CELLS
DRIVEN
MEK INHIBITION
MODELS
RESISTANCE
STRATEGY
THERAPY
3122 Cancers
Rights:


Files in this item

Total number of downloads: Loading...

Files Size Format View
Talwelkar_2019_ ... sine_kinase_signaling_.pdf 2.358Mb PDF View/Open

This item appears in the following Collection(s)

Show full item record