A subset of diffuse-type gastric cancer is susceptible to mTOR inhibitors and checkpoint inhibitors

Abstract

BackgroundMechanistic target of rapamycin (mTOR) pathway is essential for the growth of gastric cancer (GC), but mTOR inhibitor everolimus was not effective for the treatment of GCs. The Cancer Genome Atlas (TCGA) researchers reported that most diffuse-type GCs were genomically stable (GS). Pathological analysis suggested that some diffuse-type GCs developed from intestinal-type GCs.MethodsWe established patient-derived xenograft (PDX) lines from diffuse-type GCs, and searched for drugs that suppressed their growth. Diffuse-type GCs were classified into subtypes by their gene expression profiles.ResultsmTOR inhibitor temsirolimus strongly suppressed the growth of PDX-derived diffuse-type GC-initiating cells, which was regulated via Wnt-mTOR axis. These cells were microsatellite unstable (MSI) or chromosomally unstable (CIN), inconsistent with TCGA report. Diffuse-type GCs in TCGA cohort could be classified into two clusters, and GS subtype was major in cluster I while CIN and MSI subtypes were predominant in cluster II where PDX-derived diffuse-type GC cells were included. We estimated that about 9 and 55% of the diffuse-type GCs in cluster II were responders to mTOR inhibitors and checkpoint inhibitors, respectively, by identifying PIK3CA mutations and MSI condition in TCGA cohort. These ratios were far greater than those of diffuse-type GCs in cluster I or intestinal-type GCs. Further analysis suggested that diffuse-type GCs in cluster II developed from intestinal-type GCs while those in cluster I from normal gastric epithelial cells.ConclusionmTOR inhibitors and checkpoint inhibitors might be useful for the treatment of a subset of diffuse-type GCs which may develop from intestinal-type GCs.Electronic supplementary materialThe online version of this article (10.1186/s13046-019-1121-3) contains supplementary material, which is available to authorized users.

Identification of a molecular signature of prognostic subtypes in diffuse-type gastric cancer

“…3c). These results also support a distinct feature of the INT subtype regarding the response to ICI treatment according to significant enrichment of MSI or EBV along with PIK3CA and ARID1A mutations [5,[14][15][16][17].…”

“…We also observed significantly more mutations of PIK3CA [frequently found in microsatellite unstable (MSI) GCs] [14] and ARID1A (associated with MSI along with hypermutations and PD-L1 expression in cancers including GC) [15][16][17] in the INT subtype compared to the COD subtype. These results suggest distinct features of the INT subtype, including high TMB and MSI, which are typical indicators predicting the response to ICI treatment [5,18,19].…”

“…Diffuse-type GC is clinically heterogeneous and frequently exhibits extremely poor outcomes [5]. Using multiple GC patient cohorts, we carried out transcriptome and mutation profiling analyses, which identified a signature of distinct prognostic subtypes of diffuse-type GC.…”

“…The Lauren classification, stratifying GC into diffuse, intestinal, and mixed types, has been widely used in the clinical field [3,4]. Diffuse-type GC accounts for approximately 30% of GC and often exhibits more aggressive characteristics and poorer clinical outcomes than intestinal-type GC [5,6]. Therefore, there is a crucial need to molecularly characterize diffuse-type GC and identify a signature that could predict the clinical course of and suggest appropriate treatment options for diffuse-type GC.…”

“…Additionally, diffuse-type GCs can be further distinguished as the microsatellite stable and epithelial-to-mesenchymal transition (MSS/EMT) subtype, which shows the worst prognosis as demonstrated by the Asian Cancer Research Group (ACRG) [8]. Despite these defined classifications, diffuse-type GC is molecularly heterogeneous [5] because of different tumor origins among diffuse-type GCs [9]. Recent advances in molecular characterization have provided evidence that diffuse-type GC comprises molecularly distinct subtypes, including EMTassociated subtypes [4,10].…”