Journal
CANCER DISCOVERY
Volume 9, Issue 5, Pages 628-645Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2159-8290.CD-18-1489
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Categories
Funding
- University of Texas MD Anderson Cancer Center (MD Anderson) Caroline Ross Fellowship
- MD Anderson/UT-Health Graduate School of Biomedical Sciences Schissler Foundation Fellowship
- NIH National Center for Advancing Translational Sciences [TL1TR000369, UL1TR000371]
- Dr. Miriam and Sheldon G. Adelson Medical Research Foundation
- AIM at Melanoma Foundation
- NIH/NCI [R01 CA121118-06A1, 2T32CA009666-21, R01 CA121118]
- Cancer Prevention Research Institute of Texas (CPRIT) [RP170401]
- MD Anderson Multidisciplinary Research Program
- CPRIT [RP160183]
- Melanoma Research Alliance Young Investigator Award [348483]
- Dr. John M. Skibber Professorship of MD Anderson
- Robert and Lynne Grossman Family Foundation
- Michael and Patricia Booker Melanoma Research Endowment
- ASCO/CCF Young Investigator Award
- MD Anderson Melanoma SPORE Developmental Research Award [P50 CA093459]
- NIH T32 Training Grant Award [CA009666]
- HHMI (Investigator Program)
- Melanoma Research Alliance Established Investigator Award [347651]
- Metabolomics Core and Population Sciences Biorepository Core at Baylor College of Medicine
- NIH [P30 CA125123]
- CPRIT Proteomics and Metabolomics Core Facility [RP170005]
- American Cancer Society (ACS) [127430-RSG-15-105-01-CNE]
- Agilent Technologies Center of Excellence (COE) in Mass Spectrometry Collaboration at Baylor College of Medicine
- [NIH/NCIR01CA220297]
- [NIH/NCIR01CA216426]
- [NIH/NCIU01 CA167234]
- [NIH/NCIUO1 CA179674-01A1]
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There is a critical need to improve our understanding of the pathogenesis of melanoma brain metastases (MBM). Thus, we performed RNA sequencing on 88 resected MBMs and 42 patient-matched extracranial metastases; tumors with sufficient tissue also underwent whole-exome sequencing, T-cell receptor sequencing, and IHC. MBMs demonstrated heterogeneity of immune infiltrates that correlated with prior radiation and post-craniotomy survival. Comparison with patient-matched extracranial metastases identified significant immunosuppression and enrichment of oxidative phosphorylation (OXPHOS) in MBMs. Gene-expression analysis of intracranial and subcutaneous xenografts, and a spontaneous MBM model, confirmed increased OXPHOS gene expression in MBMs, which was also detected by direct metabolite profi ling and [U-(WC)-W-13]-glucose tracing in vivo. IACS-010759, an OXPHOS inhibitor currently in early-phase clinical trials, improved survival of mice bearing MAPK inhibitor-resistant intracranial melanoma xenografts and inhibited MBM formation in the spontaneous MBM model. The results provide new insights into the pathogenesis and therapeutic resistance of MBMs. SIGNIFICANCE: Improving our understanding of the pathogenesis of MBMs will facilitate the rational development and prioritization of new therapeutic strategies. This study reports the most comprehensive molecular profi ling of patient-matched MBMs and extracranial metastases to date. The data provide new insights into MBM biology and therapeutic resistance. See related commentary by Egelston and Margolin, p. 581.
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