Doxazosin, a Classic Alpha 1-Adrenoceptor Antagonist, Overcomes Osimertinib Resistance in Cancer Cells via the Upregulation of Autophagy as Drug Repurposing.

Shuhei Suzuki,Masashi Okada,Asuka Sugai,Tomomi Sanomachi,Takashi Yoshioka,Shizuka Seino,Chifumi Kitanaka,Masahiro Yamamoto,Keita Togashi

doi:10.3390/biomedicines8080273

Shuhei Suzuki, Masashi Okada + Show 7 more

Open Access

https://doi.org/10.3390/biomedicines8080273

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Journal: Biomedicines	Publication Date: Aug 5, 2020
Citations: 12	License type: CC BY 4.0

Affiliation: Yamagata University

Abstract

Osimertinib, which is a third-generation epidermal growth factor receptor tyrosine kinase inhibitor, is an important anticancer drug because of its high efficacy and excellent safety profile. However, resistance against osimertinib is inevitable; therefore, therapeutic strategies to overcome the resistance are needed. Doxazosin, a classic quinazoline-based alpha 1-adrenoceptor antagonist is used to treat hypertension and benign prostatic hyperplasia with a known safety profile. The anticancer effects of doxazosin have been examined in various types of malignancies from the viewpoint of drug repositioning or repurposing. However, it currently remains unclear whether doxazosin sensitizes cancer cells to osimertinib. Herein, we demonstrated that doxazosin induced autophagy and enhanced the anticancer effects of osimertinib on the cancer cells and cancer stem cells of non-small cell lung cancer, pancreatic cancer, and glioblastoma at a concentration at which the growth of non-tumor cells was not affected. The osimertinib-sensitizing effects of doxazosin were suppressed by 3-methyladenine, an inhibitor of autophagy, which suggested that the effects of doxazosin were mediated by autophagy. The present study provides evidence for the efficacy of doxazosin as a combination therapy with osimertinib to overcome resistance against osimertinib.

Highlights

Osimertinib, which is a third-generation epidermal growth factor tyrosine kinase inhibitor (EGFR-TKI), is an important drug in the treatment of cancer because of its strong anticancer activities and mild adverse effects [1,2]
We revealed that doxazosin induced autophagy and sensitized various types of cancer cells and cancer stem cells (CSCs) to osimertinib
We examined whether doxazosin exerts anticancer effects on the cancer cells of non-small cell lung cancer (NSCLC), pancreatic cancer, and glioblastoma

Summary

Introduction

Osimertinib, which is a third-generation epidermal growth factor tyrosine kinase inhibitor (EGFR-TKI), is an important drug in the treatment of cancer because of its strong anticancer activities and mild adverse effects [1,2]. Osimertinib is used to treat non-small cell lung cancer (NSCLC). Harboring EGFR gene mutations, such as the deletion of exon 19 and L858R mutations [1,2]. Biomedicines 2020, 8, 273 acquired resistance against osimertinib inevitably occurs through several mechanisms which include the acquisition of C797S mutations, small cell transformation, and the activation of bypass signal pathways, such as HER2 amplification, MET amplification, and PIK3CA activation mutations [3,4,5]. EGFR wild-type NSCLC, accounting for approximately 80–85% of cases, are primarily resistant to osimertinib [6,7]. EGFR signaling is dysregulated in other types of malignancies, including pancreatic cancer and glioblastoma [8,9], EGFR-TKI exhibits limited efficacy against these malignancies [10,11]. Many studies, including ours, have revealed potential targets to overcome

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