Niclosamide Overcomes Acquired Resistance to Erlotinib through Suppression of STAT3 in Non–Small Cell Lung Cancer

Abstract

The emergence of resistance to epidermal growth factor receptor (EGFR) inhibitor therapy is a major clinical problem for patients with non-small cell lung cancer (NSCLC). The mechanisms underlying tumor resistance to inhibitors of the kinase activity of EGFR are not fully understood. Here we found that inhibition of EGFR by erlotinib induces STAT3 phosphorylation at Tyr705 in association with increased Bcl2/Bcl-XL at both mRNA and protein levels in various human lung cancer cells. PTPMeg2 is a physiologic STAT3 phosphatase that can directly dephosphorylate STAT3 at the Tyr705 site. Intriguingly, treatment of cells with erlotinib results in downregulation of PTPMeg2 without activation of STAT3 kinases (i.e. JAK2 or c-Src), suggesting that erlotinib enhanced phosphorylation of STAT3 may occur, at least in part, from suppression of PTPMeg2 expression. Since elevated levels of phosphorylated STAT3 (pSTAT3), Bcl2 and Bcl-XL were observed in erlotinib-resistant lung cancer (HCC827/ER) cells as compared to erlotinib-sensitive parental HCC827 cells, we postulate that erlotinib-activated STAT3/Bcl2/Bcl-XL survival pathway may contribute to acquired resistance to erlotinib. Both blockage of Tyr705 phosphorylation of STAT3 by niclosamide and depletion of STAT3 by RNA interference in HCC827/ER cells reverses erlotinib resistance. Niclosamide in combination with erlotinib potently represses erlotinib-resistant lung cancer xenografts in association with increased apoptosis in tumor tissues, suggesting that niclosamide can restore sensitivity to erlotinib. These findings uncover a novel mechanism of erlotinib resistance and provide a novel approach to overcome resistance by blocking the STAT3/Bcl2/Bcl-XL survival signaling pathway in human lung cancer.

A Blockade of IGF Signaling Sensitizes Human Ovarian Cancer Cells to the Anthelmintic Niclosamide-Induced Anti-Proliferative and Anticancer Activities

“…Consistent with our pathway reporter assay results, Niclosamide was shown to inactivate NFκB pathway and generate reactive oxygen species in acute myelogenous leukemia stem cells [29]. Niclosamide was shown to inhibit STAT3 and consequently induced cell growth inhibition, apoptosis, and cell cycle arrest of the cancer cells with constitutively active STAT3 [81], which was shown to synergize with erlotinib against head and neck cancer [27], to overcome the acquired resistance to erlotinib in non-small cell lung cancer [19], and to reverse radioresistance of human lung cancer [20]. 100A4-induced metastasis formation in a mouse model of colon cancer was inhibited by niclosamide [17].…”

“…Niclosamide was identified as potential anticancer agent by various highthroughput screening campaigns [14]. It has been shown that Niclosamide exhibits effective anticancer activity and inhibits the growth of colon rectal cancer [15][16][17], osteosarcoma [18], lung cancer [19,20], breast cancer [21][22][23][24], prostate cancer [21,25], glioblastoma [26], head and neck cancer [27], leukemia [28,29], human uterine leiomyoma [30], and ovarian cancer [31][32][33]. Nonetheless, Niclosamide may not be used as a single agent therapy for any human cancers including ovarian cancer.…”

Niclosamide Exhibits Potent Anticancer Activity and Synergizes with Sorafenib in Human Renal Cell Cancer Cells

“…Niclosamide has been shown to exhibit anticancer activity in several types of human cancer [19,20,23,24], osteosarcoma [21], lung cancer [25,26], breast cancer [27][28][29][30], prostate cancer [27,31], glioblastoma [32], head and neck cancer [33], leukemia [34,35], human uterine leiomyoma [36], and ovarian cancer [37][38][39]. We previously showed that Niclosamide exerts its anticancer activity by targeting multiple signaling pathways in human osteosarcoma [21].…”

Repression of PDK1- and LncRNA HOTAIR-Mediated EZH2 Gene Expression Contributes to the Enhancement of Atractylenolide 1 and Erlotinib in the Inhibition of Human Lung Cancer Cells

“…Xenografts were allowed to grow until initial measurement (100-150 mm 3 ) was obtained using calipers. Mice were randomly divided into control and ATL-1 (75 mg/kg), erlotinib alone (50 mg/kg), and the combination of ATL-1 and erlotinib groups, which were administered daily via intraperitoneal injection for up to 20 days (n = 10 per group) according to previous studies [36][37][38] Next, mice were anesthetized via inhalation of 2% isoflurane. The substrate D-luciferin (Caliper Life Cellular Physiology and Biochemistry…”