The Anti-Non-Small Cell Lung Cancer Cell Activity by a mTOR Kinase Inhibitor PQR620.

Jian-Hua Zha,Zhi Hu,Han Xiao,Chun-Lin Ye,Ying-Chen Xia,Wei-Hua Xu,Ben-Tong Yu,Qin Zhang,Guo-Qiu Xu

doi:10.3389/fonc.2021.669518

Abstract

In non-small-cell lung carcinoma (NSCLC), aberrant activation of mammalian target of rapamycin (mTOR) contributes to tumorigenesis and cancer progression. PQR620 is a novel and highly-potent mTOR kinase inhibitor. We here tested its potential activity in NSCLC cells. In primary human NSCLC cells and established cell lines (A549 and NCI-H1944), PQR620 inhibited cell growth, proliferation, and cell cycle progression, as well as cell migration and invasion, while inducing significant apoptosis activation. PQR620 disrupted assembles of mTOR complex 1 (mTOR-Raptor) and mTOR complex 2 (mTOR-Rictor-Sin1), and blocked Akt, S6K1, and S6 phosphorylations in NSCLC cells. Restoring Akt-mTOR activation by a constitutively-active Akt1 (S473D) only partially inhibited PQR620-induced cytotoxicity in NSCLC cells. PQR620 was yet cytotoxic in Akt1/2-silenced NSCLC cells, supporting the existence of Akt-mTOR-independent mechanisms. Indeed, PQR620 induced sphingosine kinase 1 (SphK1) inhibition, ceramide production and oxidative stress in primary NSCLC cells. In vivo studies demonstrated that daily oral administration of a single dose of PQR620 potently inhibited primary NSCLC xenograft growth in severe combined immune deficient mice. In PQR620-treated xenograft tissues, Akt-mTOR inactivation, apoptosis induction, SphK1 inhibition and oxidative stress were detected. In conclusion, PQR620 exerted potent anti-NSCLC cell activity via mTOR-dependent and -independent mechanisms.

Highlights

Lung cancer is a leading cause of cancer-related human mortalities worldwide [1, 2]
MTOR inactivation by Akt1/2 shRNA and AZD-2014 (300 nM, 24 h) treatment failed to significantly alter sphingosine kinase 1 (SphK1) activity (Figure 5I), ceramide contents (Figure 5J) or Reactive Oxygen Species (ROS) production (Figure 5K). These results indicated that SphK1 inhibition and ROS production were unique actions by PQR620 in non-small-cell lung carcinoma (NSCLC) cells, independent of mammalian target of rapamycin (mTOR) inhibition
Overexpression, and posttranslational modifications, aberrant mTOR activation is often detected in a significant proportion of NSCLC, which is heavily implicated in tumorigenesis and cancer progression [5]

Summary

Introduction

Lung cancer is a leading cause of cancer-related human mortalities worldwide [1, 2]. NSCLC has one of the worst prognosis among all human malignancies [1, 2] with only 8-10 months of average. PQR620 Inhibits NSCLC Cells survival for advanced NSCLC patients [1, 2]. Activation of mTOR is essential for a number of core cellular behaviors, including cell growth, proliferation and motility, survival, as well as protein synthesis, autophagy inhibition, apoptosis-resistance and transcription [5,6,7,8,9]. Dysregulation and aberrant activation of mTOR is commonly detected in NSCLC, which is associated with tumorigenesis and cancer progression [5, 6]. Dysregulation and aberrant activation of mTOR is commonly detected in NSCLC, which is associated with tumorigenesis and cancer progression [5, 6]. mTOR is a validate and important therapeutic target of NSCLC [5, 6]

Methods

Results

Conclusion