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

• Published in: Cell death & disease Vol. 13; no. 7; p. 611
• Main Authors: Eggermont, Carolien, Giron, Philippe, Noeparast, Maxim, Vandenplas, Hugo, Aza-Blanc, Pedro, Gutierrez, Gustavo J., De Grève, Jacques
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 15.07.2022; Springer Nature B.V; Nature Publishing Group
• Subjects: 13/106; 13/109; 13/2; 13/31; 13/89; 13/95; 14/19; 14/35; 38/39; 38/47; 38/70; 38/77; 38/91; 631/67/1059/602; 631/67/1612/1350; 82/29; Afatinib - pharmacology; Antibodies; Biochemistry; Biomedical and Life Sciences; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - pathology; Cell Biology; Cell Culture; Cell viability; Drug resistance; Drug Resistance, Neoplasm - genetics; Drug tolerance; Drug Tolerance - genetics; Drug Tolerance - physiology; Epidermal growth factor; Epidermal growth factor receptors; ErbB Receptors - antagonists & inhibitors; ErbB Receptors - metabolism; Fibroblast growth factor 1; Fibroblast Growth Factor 1 - metabolism; Growth factors; Humans; Immunology; Life Sciences; Lung cancer; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Lung Neoplasms - pathology; Mutants; Mutation - genetics; Non-small cell lung carcinoma; Patients; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Protein-tyrosine kinase; Receptor Protein-Tyrosine Kinases - metabolism; RNA, Small Interfering - genetics; siRNA; Small cell lung carcinoma; Threonine; Tumors
• DOI: 10.1038/s41419-022-04994-4
• ISSN: 2041-4889

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.