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Clin Cancer Res. 2017 Jun 15;23(12):3168-3180. doi: 10.1158/1078-0432.CCR-17-0270. Epub 2017 Feb 13.

Transcriptional Mechanisms of Resistance to Anti-PD-1 Therapy.

Author information

1
Department of Oncology, Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland.
2
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
3
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
4
Department of Dermatology, Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland.
5
Department of Pathology, Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland.
6
Department of Surgery, Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland.
7
The Lowe Family Genomics Core, Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland.
8
Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.
9
Oncology Bioinformatics Core, Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland.
10
Laboratory of System Biology and Computational Genetics, Vavilov Institute of General Genetics, Russian Academy of Sciences, Moscow, Russia.
11
Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland.
12
Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York.
13
Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.
14
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York. stopali1@jhmi.edu iacobuzc@mskcc.org.
15
Department of Surgery, Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland. stopali1@jhmi.edu iacobuzc@mskcc.org.

Abstract

Purpose: To explore factors associated with response and resistance to anti-PD-1 therapy, we analyzed multiple disease sites at autopsy in a patient with widely metastatic melanoma who had a heterogeneous response.Materials and Methods: Twenty-six melanoma specimens (four premortem, 22 postmortem) were subjected to whole exome sequencing. Candidate immunologic markers and gene expression were assessed in 10 cutaneous metastases showing response or progression during therapy.Results: The melanoma was driven by biallelic inactivation of NF1 All lesions had highly concordant mutational profiles and copy number alterations, indicating linear clonal evolution. Expression of candidate immunologic markers was similar in responding and progressing lesions. However, progressing cutaneous metastases were associated with overexpression of genes associated with extracellular matrix and neutrophil function.Conclusions: Although mutational and immunologic differences have been proposed as the primary determinants of heterogeneous response/resistance to targeted therapies and immunotherapies, respectively, differential lesional gene expression profiles may also dictate anti-PD-1 outcomes. Clin Cancer Res; 23(12); 3168-80. ©2017 AACRSee related commentary by Wilmott et al., p. 2921.

PMID:
28193624
PMCID:
PMC5474192
DOI:
10.1158/1078-0432.CCR-17-0270
[Indexed for MEDLINE]
Free PMC Article

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