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Updated: Jan 22, 2026

Assessment of Resistance to Tyrosine Kinase Inhibitors by an Interrogation of Signal Transduction Pathways by Antibody Arrays
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Assessment of Resistance to Tyrosine Kinase Inhibitors by an Interrogation of Signal Transduction Pathways by Antibody Arrays

Published on: September 19, 2018

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

Sarang S Talwelkar1, Ashwini S Nagaraj1, Jennifer R Devlin1

  • 1Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland.

Molecular Cancer Therapeutics
|July 20, 2019
PubMed

Insights

Most non-small cell lung cancers (NSCLC) with KRAS mutations are resistant to MEK inhibitors. However, targeting ERBB signaling pathways shows promise for treating these NSCLC subtypes, suggesting ERBB network activity as a predictive biomarker.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Most non-small cell lung cancers (NSCLC) harbor mutations in KRAS, TP53, or STK11/LKB1, often rendering them untargetable with current therapies.
  • Identifying novel drug vulnerabilities in these NSCLC subtypes is critical for improving patient outcomes.

Purpose of the Study:

  • To identify drug vulnerabilities in non-small cell lung cancers (NSCLC) with KRAS mutations by combining ex vivo drug sensitivity profiling with in vivo drug response studies.
  • To investigate the role of receptor tyrosine kinase (RTK) activation in acquired resistance to MEK inhibition in NSCLC.

Main Methods:

  • Established primary adenosquamous carcinoma (ASC) and adenocarcinoma (AC) cell cultures from Kras (KL) and Kras (KP) mutant tumors.
  • Utilized conditional reprogramming for Lkb1-null cell line establishment.
  • Performed ex vivo drug sensitivity profiling and in vivo drug response studies, including clonogenic assays and analysis of RTK signaling networks.

Main Results:

  • While KRAS-mutant NSCLC cultures showed initial sensitivity to MEK inhibition, long-term assays revealed resistance mediated by adaptive activation of ERBBs (in KL cultures) or FGFR (in AC cultures).
  • Pan-ERBB inhibition demonstrated efficacy in KL cultures, particularly when combined with MEK inhibition.
  • Combinatorial MEK and FGFR inhibition suppressed clonogenicity in AC cultures.
  • In vivo studies confirmed sensitivity to pan-ERBB inhibition in KRAS-mutant NSCLC, correlating with ERBB ligand expression and receptor activation, suggesting ERBB network activity as a predictive biomarker.

Conclusions:

  • ERBB network activity can serve as a predictive biomarker for response to pan-ERBB inhibition in specific NSCLC subtypes.
  • Analysis of in situ ERBB signaling networks, combined with ex vivo drug profiling, offers a diagnostic approach to identify NSCLC tumors sensitive to ERBB network-targeted therapies.
  • Targeting adaptive RTK activation is crucial for overcoming resistance in KRAS-mutant NSCLC.

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