The EGFR-STYK1-FGF1 axis sustains functional drug tolerance to EGFR inhibitors in EGFR-mutant non-small cell lung cancer

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Non-small cell lung cancer (NSCLC) patients harboring activating mutations in epidermal growth factor receptor (EGFR) are sensitive to therapy with EGFR tyrosine kinase inhibitors (TKI). Despite remarkable clinical responses using EGFR TKI, surviving drug tolerant cells serve as a reservoir from which drug resistant tumors may emerge. This study addresses the need for improved efficacy of EGFR TKI by identifying targets involved in functional drug tolerance against them. To this aim, a high-throughput siRNA kinome screen was performed using two EGFR TKI-sensitive EGFR-mutant NSCLC cell lines in the presence/absence of the second-generation EGFR TKI afatinib. From the screen, Serine/Threonine/Tyrosine Kinase 1 (STYK1) was identified as a target that when downregulated potentiates the effects of EGFR inhibition in vitro. We found that chemical inhibition of EGFR combined with the siRNA-mediated knockdown of STYK1 led to a significant decrease in cancer cell viability and anchorage-independent cell growth. Further, we show that STYK1 selectively interacts with mutant EGFR and that the interaction is disrupted upon EGFR inhibition. Finally, we identified fibroblast growth factor 1 (FGF1) as a downstream effector of STYK1 in NSCLC cells. Accordingly, downregulation of STYK1 counteracted the afatinib-induced upregulation of FGF1. Altogether, we unveil STYK1 as a valuable target to repress the pool of surviving drug tolerant cells arising upon EGFR inhibition. Co-targeting of EGFR and STYK1 could lead to a better overall outcome for NSCLC patients.

Original languageEnglish
Article number611
Number of pages11
JournalCell & Death Disease
Issue number7
Publication statusPublished - 15 Jul 2022

Bibliographical note

© 2022. The Author(s).


  • Afatinib/pharmacology
  • Carcinoma, Non-Small-Cell Lung/drug therapy
  • Drug Resistance, Neoplasm/genetics
  • Drug Tolerance/genetics
  • ErbB Receptors/antagonists & inhibitors
  • Fibroblast Growth Factor 1/metabolism
  • Humans
  • Lung Neoplasms/drug therapy
  • Mutation/genetics
  • Protein Kinase Inhibitors/pharmacology
  • RNA, Small Interfering/genetics
  • Receptor Protein-Tyrosine Kinases/metabolism


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