Mechanism Of MTOR Kinase Inhibitor PQR620 Against Non-Small Cell Lung Cancer

In non-small-cell lung cancer(NSCLC),aberrant activation of mammalian target of rapamycin(m TOR)drives tumorigenesis and cancer progression.PQR620 is a novel and highly-potent m TOR 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 activation of apoptosis.PQR620 disrupted the assembly of m TOR complex 1(m TOR-Raptor)and m TOR complex 2(m TOR-Rictor-Sin1)and prevented the phosphorylation of Akt,S6K1 and S6 in NSCLC cells.Overexpression of continuously activated Akt1(S473D)activated Akt-m TOR signaling pathway only partially inhibited PQR620-induced cytotoxicity in NSCLC cells.PQR620 remained cytotoxic in Akt1/2-silenced NSCLC cells,suggesting that PQR620 does not fully rely on Akt-m TOR signaling for its function in inhibiting the progression of NSCLC.Indeed,PQR620 induced sphingosine kinase 1(Sph K1)inhibition,ceramide p production and oxidative stress in primary NSCLC cells.In vivo studies demonstrated that a single daily oral dose of PQR620 effectively inhibits primary NSCLC xenograft growth in severely combined immunodeficient mice.Akt-m TOR inactivation,apoptosis induction,Sph K1 inhibition and oxidative stress were detected in PQR620-treated xenograft tissues.In conclusion,PQR620 exerted potent anti-NSCLC cell activity through m TOR-dependent and-independent mechanisms.