Abstract
Tyrosine kinase inhibitors (TKIs) targeting epidermal growth factor receptor (EGFR) have clinically benefited to lung cancer patients harboring a subset of activating EGFR mutations. However, even with the remarkable therapeutic response at the initial TKI treatment, most lung cancer patients eventually have relapsed aggressive tumors due to acquired resistance to the TKIs. Here, we report that 3, 4, 5-trihydroxybenzoic acid or gallic acid (GA), a natural polyphenolic compound, shows anti-tumorigenic effects in TKI-resistant non-small cell lung cancer (NSCLC). Using both in vitro growth assay and in vivo xenograft animal model, we demonstrated tumor suppressive effect of GA was more selective for the TKI-resistant cancer compared to the TKI-sensitive one. Mechanistically, GA treatment inhibited Src-Stat3-mediated signaling and decreased the expression of Stat3-regulated tumor promoting genes, subsequently inducing apoptosis and cell cycle arrest in the TKI-resistant lung cancer but not in the TKI-sensitive one. Consistent with the in vitro results, in vivo xenograft experiments showed the TKI-resistant tumor-selective growth inhibition and suppression of Src-Stat3-dependent signaling in the GA-treated tumors isolated from the xenograft model. This finding identified an importance of Src-Stat3 signaling cascade in GA-mediated tumor-suppression activity and, more importantly, provides a novel therapeutic insight of GA for advanced TKI-resistant lung cancer.
Highlights
Lung cancer is a fatal disease leading to the highest number of cancer deaths worldwide [1, 2]
To explore therapeutic effect of gallic acid (GA) in the TKIR lung cancer, we carried out cell growth assay by treating parental and TKIR HCCC827 cells with GA or gefitinib in a dose-dependent manner
GA showed no toxicity in HBEC2KT and HBEC3KT, which were affected by gefitinib even at 0.1 μM (Figure 1D)
Summary
Lung cancer is a fatal disease leading to the highest number of cancer deaths worldwide [1, 2]. A targeted therapy blocking oncogenic EGFR is currently the only biological anti-cancer adjuvant strategy after surgery of lung cancer. As EGFR activation induces downstream signaling pathways driving tumor proliferation and/ or anti-apoptosis, targeting activated EGFR signaling by using TKIs such as gefitinib or erlotinib markedly suppresses tumor growth, leading to remarkable clinical benefit for lung cancer patients. Patients eventually acquire resistance to gefitinib or erlotinib, even with dramatic therapeutic response at the initial TKI treatment for EGFR-mutant NSCLC, leads to a clinical challenge for overcoming TKI resistance [3, 4]. Several clinical approaches to overcome TKI-resistant (TKIR) tumor progression have been developed, including radiation therapy for the region surgically resected, the combination of radiation and cytotoxic chemotherapy, or the development of generation TKIs [4].
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