Pharmacologic Targeting of S6K1 in PTEN-Deficient Neoplasia

Hongqi Liu,Xizhi Feng,Kelli N Ennis,Catherine A Behrmann,Pranjal Sarma,Tony T Jiang,Satoshi Kofuji,Liang Niu,Yiwen Stratton,Hala Elnakat Thomas,Sang-Oh Yoon,Atsuo T Sasaki,David R Plas

doi:10.1016/j.celrep.2017.02.022

Abstract

Genetic S6K1 inactivation can induce apoptosis in PTEN-deficient cells. We analyzed the therapeutic potential of S6K1 inhibitors in PTEN-deficient Tcell leukemia and glioblastoma. Results revealed that the S6K1 inhibitor LY-2779964 was relatively ineffective as a single agent, while S6K1-targeting AD80 induced cytotoxicity selectively in PTEN-deficient cells. Invivo, AD80 rescued 50% of mice transplanted with PTEN-deficient leukemia cells. Cells surviving LY-2779964 treatment exhibited inhibitor-induced S6K1 phosphorylation due to increased mTOR-S6K1 co-association, which primed the rapid recovery of S6K1 signaling. In contrast, AD80 avoided S6K1 phosphorylation and mTOR co-association, resulting in durable suppression of S6K1-induced signaling and protein synthesis. Kinome analysis revealed that AD80 coordinately inhibits S6K1 together with the TAM family tyrosine kinase AXL. TAM suppression by BMS-777607 or genetic knockdown potentiated cytotoxic responses to LY-2779964 in PTEN-deficient glioblastoma cells. These results reveal that combination targeting of S6K1 andTAMs is a potential strategy for treatment of PTEN-deficient malignancy.

Highlights

Inactivation of the phosphatidylinositol 3′-phosphatase PTEN as a result of genomic mutation, epigenetic silencing, and/or non-coding RNA regulation is a frequent event in glioblastoma and T acute lymphoblastic leukemia (Cerami et al, 2012; Gao et al, 2013; Gutierrez et al, 2009; Song et al, 2012, Cancer Genome Atlas Research, 2008 #1422)
We investigated the cytotoxic effects of recently described S6 kinase 1 (S6K1) inhibitors AD80 and LY-2779964
murine embryonic fibroblast (MEF) treated with TNFα in combination with inhibitors of protein synthesis such as cycloheximide (Figure S1b) or AD80 undergo apoptosis (Lee et al, 2000)

Summary

Introduction

Inactivation of the phosphatidylinositol 3′-phosphatase PTEN as a result of genomic mutation, epigenetic silencing, and/or non-coding RNA regulation is a frequent event in glioblastoma and T acute lymphoblastic leukemia (Cerami et al, 2012; Gao et al, 2013; Gutierrez et al, 2009; Song et al, 2012, Cancer Genome Atlas Research, 2008 #1422). S6K1 regulates translation in a non-catalytic manner through its phosphorylation-dependent association with the eIF3 complex (Holz et al, 2005). We previously showed that genetic inactivation of S6K1 in PTEN-deficient hematopoietic cells reduced glucose-dependent cell survival and significantly delayed the incidence of leukemia in vivo (Tandon et al, 2011). The absence of S6K1 reduced the incidence of adrenal tumors in PTEN+/− mice (Nardella et al, 2011). These results indicated that development of S6K1 targeted therapeutics would be beneficial for treatment of PTEN-deficient malignancy

Results

Discussion

Conclusion