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Ann Oncol. 2017 Mar 1;28(3):547-554. doi: 10.1093/annonc/mdw669.

Rapamycin-insensitive companion of mTOR (RICTOR) amplification defines a subset of advanced gastric cancer and is sensitive to AZD2014-mediated mTORC1/2 inhibition.

Author information

1
Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
2
The Angeles Clinic and Research Institute, Los Angeles, USA.
3
Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, USA.
4
Samsung Genome Institute, Samsung Medical Center, Seoul, Korea.
5
Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
6
The Innovative Cancer Medicine Institute, Samsung Medical Center, Seoul, Korea.

Abstract

Background:

Targeting oncogenic genomic aberrations is an established therapeutic strategy in multiple tumor types. Molecular classification has uncovered a number of novel targets, and rapamycin-insensitive companion of mTOR (RICTOR) amplification has been identified in lung cancer. Further investigation assessing the therapeutic potential of RICTOR amplification as a novel target across advanced cancers is needed.

Patients and methods:

Tumor samples from 640 patients with metastatic solid tumors, primarily gastrointestinal and lung cancers were prospectively subjected to a next-generation sequencing (NGS) assay to identify molecular targets. Samples with NGS-detected RICTOR amplification were confirmed with FISH. A RICTOR-amplified patient-derived cell (PDC) line was generated and used to investigate the effectiveness of selective AKT, mTORC1, and mTORC1/2 inhibition.

Results:

NGS identified 13 (2%) of 640 patients with RICTOR-amplified tumors (6 gastric, 3 NSCLC, 1 SCLC, 1 CRC, 1 sarcoma, 1 MUO). Of the 13 patients, seven patients had RICTOR protein overexpression by IHC. The prevalence of RICTOR amplification in gastric cancer by NGS was 3.8% (6/160). FISH testing confirmed amplification (RICTOR/control‚ÄČ>2) in 5/13 (38%) of samples, including four gastric cancers and one lung cancer. Treatment of a RICTOR amplified PDC with a selective AKT (AZD5363), selective mTORC1 (everolimus), dual mTORC1/2 (AZD2014), and the multi-target kinase inhibitor pazopanib demonstrated preferential sensitivity to the mTORC1/2 inhibitor (AZD2014). Knockdown of RICTOR reversed PDC sensitivity to AZD2014, validating the importance of RICTOR amplification to the PDC line.

Conclusions:

RICTOR amplification is a rare but therapeutically relevant genomic alteration across solid tumors. Our results support further pre-clinical and clinical investigation with AZD2014 in RICTOR amplified gastric cancer and highlights the importance of genomic profiling.

KEYWORDS:

AZD2014; RICTOR; gastric cancer; mTORC1/2; next-generation sequencing

PMID:
28028034
DOI:
10.1093/annonc/mdw669
[Indexed for MEDLINE]

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