American Association for Cancer Research
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15357163mct180573-sup-202557_3_supp_5603345_ptlhyg.pdf (1.08 MB)

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

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journal contribution
posted on 2023-04-03, 16:00 authored by Sarang S. Talwelkar, Ashwini S. Nagaraj, Jennifer R. Devlin, Annabrita Hemmes, Swapnil Potdar, Elina A. Kiss, Pipsa Saharinen, Kaisa Salmenkivi, Mikko I. Mäyränpää, Krister Wennerberg, Emmy W. Verschuren

Supplementary text and figures

Funding

Laboratory Animal Centre

FIMM Digital Microscopy and Molecular pathology unit

University of Helsinki

Integrative Life Science doctoral program

European Union's Seventh Framework Programme

Academy of Finland

Sigrid Juselius Foundation

Novo Nordisk Foundation

Orion-Farmos Foundation

History

ARTICLE ABSTRACT

Most non–small cell lung cancers (NSCLC) contain nontargetable 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/+;Lkb1fl/fl (KL) tumors or AC cultures from KrasG12D/+;p53fl/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 cultures. Furthermore, pan-ERBB inhibition reduced the clonogenicity 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.