Olmutinib (HM61713) reversed multidrug resistance by inhibiting the activity of ATP-binding cassette subfamily G member 2 in vitro and in vivo

Zhiqiang Zhang; Xiaoran Guo; Kenneth K W To; Zhen Chen; Xiaona Fang; Min Luo; Chunling Ma; Jianhua Xu; Shirong Yan; Liwu Fu

doi:10.1016/j.apsb.2018.06.002

Olmutinib (HM61713) reversed multidrug resistance by inhibiting the activity of ATP-binding cassette subfamily G member 2 in vitro and in vivo

Acta Pharm Sin B. 2018 Jul;8(4):563-574. doi: 10.1016/j.apsb.2018.06.002. Epub 2018 Jun 15.

Authors

Zhiqiang Zhang^{1

2}, Xiaoran Guo^{1

3}, Kenneth K W To⁴, Zhen Chen¹, Xiaona Fang¹, Min Luo¹, Chunling Ma^{1

2}, Jianhua Xu², Shirong Yan³, Liwu Fu¹

Affiliations

¹ Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China.
² School of Pharmacy, Fujian Medical University, Fuzhou 350108, China.
³ Hubei University of Medicine, Shiyan 442000, China.
⁴ School of Pharmacy, Faculty of Medicine, the Chinese University of Hong Kong, Hong Kong, China.

Abstract

Overexpressing of ATP-binding cassette (ABC) transporters is the essential cause of multidrug resistance (MDR), which is a significant hurdle to the success of chemotherapy in many cancers. Therefore, inhibiting the activity of ABC transporters may be a logical approach to circumvent MDR. Olmutinib is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), which has been approved in South Korea for advanced EGFR T790M-positive non-small cell lung cancer (NSCLC). Here, we found that olmutinib significantly increased the sensitivity of chemotherapy drug in ABCG2-overexpressing cells. Furthermore, olmutinib could also increase the retention of doxorubicin (DOX) and rhodamine 123 (Rho 123) in ABC transporter subfamily G member 2 (ABCG2)-overexpressing cells. In addition, olmutinib was found to stimulate ATPase activity and inhibit photolabeling of ABCG2 with [¹²⁵I]-iodoarylazidoprazosin (IAAP). However, olmutinib neither altered ABCG2 expression at protein and mRNA levels nor blocked EGFR, Her-2 downstream signaling of AKT and ERK. Importantly, olmutinib enhanced the efficacy of topotecan on the inhibition of S1-MI-80 cell xenograft growth. All the results suggest that olmutinib reverses ABCG2-mediated MDR by binding to ATP bind site of ABCG2 and increasing intracellular chemotherapeutic drug accumulation. Our findings encouraged to further clinical investigation on combination therapy of olmutinib with conventional chemotherapeutic drugs in ABCG2-overexpressing cancer patients.

Keywords: ABC, adenosine triphosphate (ATP)-binding cassette; ABCG2; ABCG2, ABC transporter subfamily G member 2; ATPase; Chemotherapy; DDP, cisplatin; DMEM, Dulbecco׳s modified Eagle׳s medium; DMSO, dimethyl sulfoxide; DOX, doxorubicin; FTC, fumitremorgin C; IAAP, iodoarylazidoprazosin; MDR, multidrug resistance; MTT, 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyltetrazoliumbromide; MX, methotrexate; Multidrug resistance; Olmutinib; PCR, polymerase chain reaction; Rho 123, rhodamine 123; TKI, tyrosine kinase inhibitor; Tyrosine kinase inhibitor; VRP, verapamil.