Optimize the combination regimen of Trastuzumab and Nab-paclitaxel in HER2-positive tumors via modulating Caveolin-1 expression by lovastatin

Canyu Yang; Shumin Fan; Xing Wang; Wei Liu; Long Yang; Bing He; Wenbing Dai; Hua Zhang; Xueqing Wang; Qiang Zhang

doi:10.1016/j.ajps.2022.06.002

Optimize the combination regimen of Trastuzumab and Nab-paclitaxel in HER2-positive tumors via modulating Caveolin-1 expression by lovastatin

Asian J Pharm Sci. 2022 Aug;17(5):697-712. doi: 10.1016/j.ajps.2022.06.002. Epub 2022 Jul 28.

Authors

Canyu Yang¹, Shumin Fan², Xing Wang¹, Wei Liu³, Long Yang², Bing He^{2

4}, Wenbing Dai², Hua Zhang², Xueqing Wang^{1

2}, Qiang Zhang^{1

2

4}

Affiliations

¹ Department of Pharmacy Administration and Clinical Pharmacy, School of Pharmaceutical Science, Peking University, Beijing 100191, China.
² Beijing Key Laboratory of Molecular Pharmaceutics, New Drug Delivery Systems, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
³ Department of Pharmacy, Peking University Third Hospital, Beijing, 100083, China.
⁴ State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, China.

Abstract

The combination regimen of trastuzumab (Tras) plus Nab-paclitaxel (Nab) is recommended to treat HER2-positive (HER2⁺) cancers. However, they exert effects in different mechanisms: Tras need to stay on cell membranes, while Nab need to be endocytosed, therefore the concurrent combination regimen may not be the best one in HER2⁺ tumors treatment. Caveolin-1 (Cav-1) is a key player in mediating their endocytosis and is associated with their efficacy, but few researches noticed the opposite effect of Cav-1 expression on the combination efficacy. Herein, we systematically studied the Cav-1 expression level on the combination efficacy and proposed an optimized and clinically feasible combination regimen for HER2⁺ Cav-1^High tumor treatment. In the regimen, lovastatin (Lova) was introduced to modulate the Cav-1 expression and the results indicated that Lova could downregulate Cav-1 expression, increase Tras retention on cell membrane and enhance the in vitro cytotoxicity of Tras in HER2⁺ Cav-1^High cells but not in HER2⁺ Cav-1^Low cells. Therefore, by exchanging the dosing sequence of Nab and Tras, and by adding Lova at appropriate time points, the precise three-drug-sequential regimen (PTDS, Nab(D1)-Lova(D2)-Lova & Tras(D2+12 h)) was established. Compared with the concurrent regimen, the PTDS regimen exhibited a higher in vitro cytotoxicity and a stronger tumor growth inhibition in HER2⁺ Cav-1^High tumors, which might be a promising combination regimen for these patients in clinics.

Keywords: Caveolin-1; Combination regimen optimization; Nab-paclitaxel; Trastuzumab.