Abstract
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are approved treatments for non-small-cell lung cancer (NSCLC) patients harboring activating EGFR mutations. The EGFR C797S mutation is one of the known acquired-resistance mutations to the latest third-generation TKIs. At present, there are no clear options for treating patients who acquire resistance to third-generation TKIs. The acquisition of the EGFR C797S mutation was shown to upregulate the expression of AXL, a receptor tyrosine kinase of the TAM (TYRO3-AXL-MER) family, and the suppression of AXL is effective in reducing the growth of NSCLC cells harboring EGFR C797S. As quercetin was recently shown to inhibit AXL, quercetin may be effective in treating NSCLC cells harboring the EGFR C797S mutation. In this work, the cytotoxic effects of quercetin and its ability to inhibit tumor growth were examined in TKI-resistant NSCLC cells harboring the EGFR C797S mutation. We demonstrated that quercetin exhibited potent cytotoxic effects on NSCLC cells harboring the EGFR C797S mutation by inhibiting AXL and inducing apoptosis. Quercetin inhibited the tumor growth of xenografted NSCLC cells harboring the EGFR C797S mutation and appeared to act synergistically with brigatinib to inhibit of tumor growth in vivo. In summary, herein, we revealed that quercetin is an effective inhibitor for the treatment of non-small-cell lung cancer harboring the EGFR C797S mutation.
Highlights
Lung cancer remains the leading cause of cancer-related death worldwide, and nonsmall-cell lung cancer (NSCLC) is the most common type [1]
To evaluate the feasibility of using quercetin (Figure 1A) in the treatment of TKIresistant NSCLCs, we examined the cytotoxic effects of quercetin on NSCLC cells, including A549, H1975 (EGFR L858R+ T790M) and H1975-MS35
H1975 cells are sensitive to third-generation tyrosine kinase inhibitors (TKIs) (AZD9291), while the acquisition of the epidermal growth factor receptor (EGFR) C797S mutation in H1975-MS35 renders the cells resistant to AZD9291 treatment [7]
Summary
Lung cancer remains the leading cause of cancer-related death worldwide, and nonsmall-cell lung cancer (NSCLC) is the most common type [1]. Targeted therapy designed to circumvent the epidermal growth factor receptor (EGFR) using tyrosine kinase inhibitors (TKIs) is a standard treatment for NSCLC patients harboring activating EGFR mutations [2]. Activating mutations in EGFR occur in 10–20% of Caucasian patients and in 30–40% of. First- and second-generation TKIs are reversible or irreversible inhibitors that interact with the ATP-binding sites in the EGFR kinase domain, blocking the downstream signaling of EGFR. TKI resistance within one year, most commonly due to the EGFR T790M mutation [4,5]. The third-generation TKI AZD9291 is highly active against the T790M mutation in NSCLC
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