Abstract
BackgroundAlthough EGFR tyrosine kinase inhibitors (EGFR-TKIs) are beneficial to lung adenocarcinoma patients with sensitive EGFR mutations, resistance to these inhibitors induces a cancer stem cell (CSC) phenotype. Here, we clarify the function and molecular mechanism of shisa3 as a suppressor that can reverse EGFR-TKI resistance and inhibit CSC properties.MethodsThe suppresser genes involved in EGFR-TKI resistance were identified and validated by transcriptome sequencing, quantitative real-time PCR (qRT-PCR) and immunohistochemistry. Biological function analyses, cell half maximal inhibitory concentration (IC50), self-renewal, and migration and invasion capacities, were detected by CCK8, sphere formation and Transwell assays. Tumorigenesis and therapeutic effects were investigated in nonobese diabetic/severe combined immunodeficiency (nod-scid) mice. The underlying mechanisms were explored by Western blot and immunoprecipitation analyses.ResultsWe found that low expression of shisa3 was related to EGFR-TKI resistance in lung adenocarcinoma patients. Ectopic overexpression of shisa3 inhibited CSC properties and the cell cycle in the lung adenocarcinoma cells resistant to gefitinib/osimertinib. In contrast, suppression of shisa3 promoted CSC phenotypes and the cell cycle in the cells sensitive to EGFR-TKIs. For TKI-resistant PC9/ER tumors in nod-scid mice, overexpressed shisa3 had a significant inhibitory effect. In addition, we verified that shisa3 inhibited EGFR-TKI resistance by interacting with FGFR1/3 to regulate AKT/mTOR signaling. Furthermore, combinational administration of inhibitors of FGFR/AKT/mTOR and cell cycle signaling could overcome EGFR-TKI resistance associated with shisa3-mediated CSC capacities in vivo.ConclusionTaken together, shisa3 was identified as a brake to EGFR-TKI resistance and CSC characteristics, probably through the FGFR/AKT/mTOR and cell cycle pathways, indicating that shisa3 and concomitant inhibition of its regulated signaling may be a promising therapeutic strategy for reversing EGFR-TKI resistance.
Highlights
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-Tyrosine kinase inhibitor (TKI)) have been an effective therapy for lung adenocarcinoma patients with activating mutations; therapeutic resistance to EGFR-TKIs inevitably develops [1]
We demonstrated that patients with high expression of shisa3 have a better response to EGFR-TKIs, indicating that shisa3 may be used to predict the efficacy of TKI therapy in lung adenocarcinoma patients
We screened and verified that shisa3, as a suppressor, prevents EGFRTKI resistance and suppresses the cancer stem cells (CSCs) phenotype in lung adenocarcinoma as follows: (1) Lung adenocarcinoma patients with high expression of shisa3 had a better response to EGFR-TKIs, indicating that shisa3 may be used to predict the efficacy of TKI therapy
Summary
EGFR tyrosine kinase inhibitors (EGFR-TKIs) have been an effective therapy for lung adenocarcinoma patients with activating mutations; therapeutic resistance to EGFR-TKIs inevitably develops [1]. As a tumor suppressor, has been discovered to antagonize the CSC-associated Wnt pathway and FGF signaling by interacting with immature forms of their receptors [7]. An essential transcriptional factor of CSCs, was upregulated after FGFR1 activation [8], and FGFR1 signaling has been shown to contribute to the maintenance of CSC properties by interacting with the Hippo/YAP1 pathway in lung cancer [9]. EGFR tyrosine kinase inhibitors (EGFR-TKIs) are beneficial to lung adenocarcinoma patients with sensitive EGFR mutations, resistance to these inhibitors induces a cancer stem cell (CSC) phenotype. We clarify the function and molecular mechanism of shisa as a suppressor that can reverse EGFR-TKI resistance and inhibit CSC properties
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