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

Sarang S. Talwelkar, Ashwini S. Nagaraj, Jennifer R. Devlin, Annabrita Hemmes, Swapnil Potdar, Elina A. Kiss, Pipsa Saharinen, Kaisa Maria Salmenkivi, Mikko I. Mäyränpää, Krister Wennerberg, Emmy Verschuren

Research output: Contribution to journalArticleScientificpeer-review

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.

Original languageEnglish
JournalMolecular Cancer Therapeutics
Volume18
Issue number10
Pages (from-to)1863-1874
Number of pages12
ISSN1535-7163
DOIs
Publication statusPublished - Oct 2019
MoE publication typeA1 Journal article-refereed

Fields of Science

  • ADENOCARCINOMA
  • BIOLOGY
  • CARCINOMA
  • CONDITIONALLY REPROGRAMMED CELLS
  • DRIVEN
  • MEK INHIBITION
  • MODELS
  • RESISTANCE
  • STRATEGY
  • THERAPY
  • 3122 Cancers

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