Abstract
BackgroundHER3 mediates drug resistance against epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs), resulting in tumor relapse in lung cancers. Previously, we demonstrated that EGFR induces HER3 overexpression, which facilitates the formation of cancer stem-like tumorspheres. However, the cellular mechanism through which EGFR regulates HER3 expression remains unclear. We hypothesized that EGFR downstream of STAT3 participates in HER3 expression because STAT3 contributes to cancer stemness and survival of EGFR-TKI resistant cancers.MethodsFirst, RNAseq was used to uncover potential genes involved in the formation of lung cancer HCC827-derived stem-like tumorspheres. EGFR-positive lung cancer cell lines, including HCC827, A549, and H1975, were individually treated with a panel containing 172 therapeutic agents targeting stem cell-associated genes to search for potential agents that could be applied against EGFR-positive lung cancers. In addition, gene knockdown and RNAseq were used to investigate molecular mechanisms through which STAT3 regulates tumor progression and the survival in lung cancer.ResultsBBI608, a STAT3 inhibitor, was a potential therapeutic agent that reduced the cell viability of EGFR-positive lung cancer cell lines. Notably, the inhibitory effects of BBI608 were similar with those associated with YM155, an ILF3 inhibitor. Both compounds reduced G9a-mediated HER3 expression. We also demonstrated that STAT3 upregulated G9a to silence miR-145-5p, which exacerbated HER3 expression in this study.ConclusionsThe present study revealed that BBI608 could eradicate EGFR-positive lung cancers and demonstrated that STAT3 enhanced the expression of HER3 through miR-145-5p repression by G9a, indicating that STAT3 is a reliable therapeutic target against EGFR-TKI-resistant lung cancers.
Highlights
HER3 mediates drug resistance against epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs), resulting in tumor relapse in lung cancers
The present study revealed the role of the transcriptional repression of miRNAs, such as miR-145-5p, by the STAT3-G9a axis in EGFR-positive lung cancers, which exacerbated HER3 expression and led to EGFR-TKI resistance
HER3 overexpressed in HCC827-derived stem-like tumorspheres To validate that HER3 was overexpressed in lung cancer stem cells, we cultured lung cancer HCC827 cells in the serum-free medium described in Methods and Materials to develop an artificial stem-like cancer model (Fig. 1a), which expressed a high level of CD133, as demonstrated previously [18]
Summary
HER3 mediates drug resistance against epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs), resulting in tumor relapse in lung cancers. The overexpression and activation of the epidermal growth factor receptor (EGFR), a transmembrane receptor tyrosine kinase that belongs to the ERBB family, facilitates tumor survival, proliferation, and cancer stemness in lung cancer [1, 2]. In addition to KRAS and EGFR T790 mutations, the expression of oncogenes, including MET [5,6,7], HER2 (ERBB2) [8], and epidermal growth factor receptor 3 (HER3, ERBB3) [5, 9, 10], is associated with drug resistance against EGFR-TKIs and leads to tumor recurrence in lung cancers. Constitutive overexpression of HER2 forms dimerization with HER3, leading to the downstream activation of PI3K signaling and tumor survival [12, 13] Such results indicate that HER3 causes EGFR-TKI resistance. It is vital to explore the molecular mechanism through which HER3 expression is regulated in EGFRpositive lung cancers
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