Multiregion Quantification of Extracellular Signal-regulated Kinase Activity in Renal Cell Carcinoma

Christian R Hoerner; Rustin Massoudi; Thomas J Metzner; Laurel Stell; Jennifer J O'Rourke; Christina S Kong; Joanna E Liliental; James D Brooks; Chiara Sabatti; John T Leppert; Alice C Fan

doi:10.1016/j.euo.2018.09.011

Multiregion Quantification of Extracellular Signal-regulated Kinase Activity in Renal Cell Carcinoma

Eur Urol Oncol. 2020 Jun;3(3):360-364. doi: 10.1016/j.euo.2018.09.011. Epub 2018 Nov 20.

Authors

Affiliations

¹ Division of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA; The Kidney Cancer Research Program, Stanford University School of Medicine, Stanford, CA, USA.
² The Kidney Cancer Research Program, Stanford University School of Medicine, Stanford, CA, USA; Department of Urology, Stanford University School of Medicine, Stanford, CA, USA.
³ The Kidney Cancer Research Program, Stanford University School of Medicine, Stanford, CA, USA; Department of Urology, Stanford University School of Medicine, Stanford, CA, USA; Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA.
⁴ Department of Biomedical Data Science, Stanford University School of Medicine, Stanford, CA, USA.
⁵ Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA; Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA.
⁶ Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA; Translational Applications Service Center (TASC) and Translational Research and Applied Medicine (TRAM) Program, Stanford University School of Medicine, Stanford, CA, USA.
⁷ The Kidney Cancer Research Program, Stanford University School of Medicine, Stanford, CA, USA; Department of Urology, Stanford University School of Medicine, Stanford, CA, USA; Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA; Bio-X, Stanford University, Stanford, CA, USA.
⁸ Department of Biomedical Data Science, Stanford University School of Medicine, Stanford, CA, USA; Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA; Bio-X, Stanford University, Stanford, CA, USA; Department of Statistics, Stanford University, Stanford, CA, USA.
⁹ The Kidney Cancer Research Program, Stanford University School of Medicine, Stanford, CA, USA; Department of Urology, Stanford University School of Medicine, Stanford, CA, USA; Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA; Bio-X, Stanford University, Stanford, CA, USA; Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA; Division of Nephrology, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA. Electronic address: [email protected].
¹⁰ Division of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA; The Kidney Cancer Research Program, Stanford University School of Medicine, Stanford, CA, USA; Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA; Bio-X, Stanford University, Stanford, CA, USA. Electronic address: [email protected].

Abstract

To personalize treatment for renal cell carcinoma (RCC), it would be ideal to confirm the activity of druggable protein pathways within individual tumors. We have developed a high-resolution nanoimmunoassay (NIA) to measure protein activity with high precision in scant specimens (eg, fine needle aspirates [FNAs]). Here, we used NIA to determine whether protein activation varied in different regions of RCC tumors. Since most RCC therapies target angiogenesis by inhibiting the vascular endothelial growth factor (VEGF) receptor, we quantified phosphorylation of extracellular signal-regulated kinase (ERK), a downstream effector of the VEGF signaling pathway. In 90 ex vivo FNA biopsies sampled from multiple regions of 38 primary clear cell RCC tumors, ERK phosphorylation differed among patients. In contrast, within individual patients, we found limited intratumoral heterogeneity of ERK phosphorylation. Our results suggest that measuring ERK in a single FNA may be representative of ERK activity in different regions of the same tumor. As diagnostic and therapeutic protein biomarkers are being sought, NIA measurements of protein signaling may increase the clinical utility of renal mass biopsy and allow for the application of precision oncology for patients with localized and advanced RCC. PATIENT SUMMARY: In this report, we applied a new approach to measure the activity of extracellular signal-regulated kinase (ERK), a key cancer signaling protein, in different areas within kidney cancers. We found that ERK activity varied between patients, but that different regions within individual kidney tumors showed similar ERK activity. This suggests that a single biopsy of renal cell carcinoma may be sufficient to measure protein signaling activity to aid in precision oncology approaches.

Keywords: Extracellular signal-regulated kinase; Fine needle aspirate; Intertumor heterogeneity; Intratumor heterogeneity; Kidney cancer; Phosphorylation; Protein signaling; Renal cell carcinoma.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Carcinoma, Renal Cell / chemistry
Carcinoma, Renal Cell / enzymology*
Carcinoma, Renal Cell / pathology
Extracellular Signal-Regulated MAP Kinases / analysis
Extracellular Signal-Regulated MAP Kinases / metabolism*
Humans
Kidney Neoplasms / chemistry
Kidney Neoplasms / enzymology*
Kidney Neoplasms / pathology

Substances

Extracellular Signal-Regulated MAP Kinases

Abstract

Publication types

MeSH terms

Substances

Grants and funding