Clinical, molecular, metabolic, and immune features associated with oxidative phosphorylation in melanoma brain metastases

Grant M Fischer; Renato A Guerrieri; Qianghua Hu; Aron Y Joon; Swaminathan Kumar; Lauren E Haydu; Jennifer L McQuade; Y N Vashisht Gopal; Barbara Knighton; Wanleng Deng; Courtney W Hudgens; Alexander J Lazar; Michael T Tetzlaff; Michael A Davies

doi:10.1093/noajnl/vdaa177

Clinical, molecular, metabolic, and immune features associated with oxidative phosphorylation in melanoma brain metastases

Neurooncol Adv. 2021 Jan 6;3(1):vdaa177. doi: 10.1093/noajnl/vdaa177. eCollection 2021 Jan-Dec.

Authors

Grant M Fischer¹, Renato A Guerrieri¹, Qianghua Hu¹, Aron Y Joon², Swaminathan Kumar¹, Lauren E Haydu³, Jennifer L McQuade¹, Y N Vashisht Gopal¹, Barbara Knighton¹, Wanleng Deng¹, Courtney W Hudgens^{4

5}, Alexander J Lazar^{4

5

6}, Michael T Tetzlaff^{4

5}, Michael A Davies^{4

1

6

7}

Affiliations

¹ Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
² Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
³ Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
⁴ Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
⁵ Department of Pathology/Lab Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
⁶ Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
⁷ Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Abstract

Background: Recently, we showed that melanoma brain metastases (MBMs) are characterized by increased utilization of the oxidative phosphorylation (OXPHOS) metabolic pathway compared to melanoma extracranial metastases (ECMs). MBM growth was inhibited by a potent direct OXPHOS inhibitor, but observed toxicities support the need to identify alternative therapeutic strategies. Thus, we explored the features associated with OXPHOS to improve our understanding of the pathogenesis and potential therapeutic vulnerabilities of MBMs.

Methods: We applied an OXPHOS gene signature to our cohort of surgically resected MBMs that had undergone RNA-sequencing (RNA-seq) (n = 88). Clustering by curated gene sets identified MBMs with significant enrichment (High-OXPHOS; n = 21) and depletion (Low-OXPHOS; n = 25) of OXPHOS genes. Clinical data, RNA-seq analysis, and immunohistochemistry were utilized to identify significant clinical, molecular, metabolic, and immune associations with OXPHOS in MBMs. Preclinical models were used to further compare melanomas with High- and Low-OXPHOS and for functional validation.

Results: High-OXPHOS MBMs were associated with shorter survival from craniotomy compared to Low-OXPHOS MBMs. High-OXPHOS MBMs exhibited an increase in glutamine metabolism, and treatment with the glutaminase inhibitor CB839 improved survival in mice with MAPKi-resistant, High-OXPHOS intracranial xenografts. High-OXPHOS MBMs also exhibited a transcriptional signature of deficient immune activation, which was reversed in B16-F10 intracranial tumors with metformin treatment, an OXPHOS inhibitor.

Conclusions: OXPHOS is associated with distinct clinical, molecular, metabolic, and immune phenotypes in MBMs. These associations suggest rational therapeutic strategies for further testing to improve outcomes in MBM patients.

Keywords: brain metastases; immune therapy; melanoma; oxidative phosphorylation; targeted therapy.

Grants and funding

TL1 TR003169/TR/NCATS NIH HHS/United States