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

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

doi:10.18632/oncotarget.13362

Nneha Sakre, Pingfu Fu + Show 5 more

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https://doi.org/10.18632/oncotarget.13362

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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.

Highlights

Lung cancer is divided into two disease types: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), based upon the histologic appearance of the cancer cells and the behavior of the disease
RICTOR amplification ranged from a CNV of 6 to 20; a plot of tumor copy number variation (CNV) demonstrating high, focal RICTOR amplification is shown in Figure 1C
Because of its potential as a novel therapeutic target in Small cell lung cancer (SCLC), we focused on RICTOR amplification in all subsequent studies

Summary

Introduction

Lung cancer is divided into two disease types: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), based upon the histologic appearance of the cancer cells and the behavior of the disease. SCLC makes up about 15 percent of all lung cancers and is the subtype most closely associated with cigarette smoking [1]. SCLC is an aggressive cancer that tends to grow and spread quickly. The aggressive and distant spread of SCLC led the Veterans Administration Lung Study Group in 1957 to create a dichotomized staging system termed limited stage (LS), characterized by a tumor volume encompassed in one radiation portal, and extensive stage (ES), encompassing all forms of metastatic disease [2]. Because most SCLC patients present with metastatic disease, treatment remains platinum-based chemotherapy and surgery is rarely performed (

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