Oncotarget

Research Papers:

RICTOR amplification identifies a subgroup in small cell lung cancer and predicts response to drugs targeting mTOR

Nneha Sakre, Gary Wildey, Mohadese Behtaj, Adam Kresak, Michael Yang, Pingfu Fu and Afshin Dowlati _

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Oncotarget. 2017; 8:5992-6002. https://doi.org/10.18632/oncotarget.13362

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Abstract

Nneha Sakre1,2, Gary Wildey1,2, Mohadese Behtaj3, Adam Kresak1,3, Michael Yang3, Pingfu Fu4, Afshin Dowlati1,2

1Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio, 44106 USA

2Division of Hematology and Oncology, University Hospitals Cleveland Medical Center, Cleveland, Ohio, 44106 USA

3Department of Pathology, University Hospitals Cleveland Medical Center, Cleveland, Ohio, 44106 USA

4Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio, 44106 USA

Correspondence to:

Afshin Dowlati, email: afshin.dowlati@case.edu

Keywords: RICTOR, mTORC1/2 inhibitors, CNV, amplification, small cell lung cancer

Received: May 27, 2016     Accepted: October 26, 2016     Published: November 15, 2016

ABSTRACT

Small cell lung cancer (SCLC) is an aggressive cancer that represents ~15% of all lung cancers. Currently there are no targeted therapies to treat SCLC. Our genomic analysis of a metastatic SCLC cohort identified recurrent RICTOR amplification. Here, we examine the translational potential of this observation. RICTOR was the most frequently amplified gene observed (~14% patients), and co-amplified with FGF10 and IL7R on chromosome 5p13. RICTOR copy number variation correlated with RICTOR protein expression in SCLC cells. In parallel, cells with RICTOR copy number (CN) gain showed increased sensitivity to three mTOR inhibitors, AZD8055, AZD2014 and INK128 in cell growth assays, with AZD2014 demonstrating the best inhibition of downstream signaling. SCLC cells with RICTOR CN gain also migrated more rapidly in chemotaxis and scratch wound assays and were again more sensitive to mTOR inhibitors. The overall survival in SCLC patients with RICTOR amplification was significantly decreased (p = 0.021). Taken together, our results suggest that SCLC patients with RICTOR amplification may constitute a clinically important subgroup because of their potential response to mTORC1/2 inhibitors.


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