Activation of the c-Met pathway occurs in a range of malignancies, including papillary renal cell carcinoma (RCC). Its activity in clear cell RCC is less clear. We investigated c-Met expression and inhibition in a large cohort of RCC tumors and cell lines.
c-Met protein expression was determined by automated quantitative analysis (AQUA) on a tissue microarray (TMA) constructed from 330 RCC tumors paired with adjacent normal renal tissue. c-Met expression and selective inhibition with SU11274 and ARQ 197 were studied in clear cell RCC cell lines.
Higher c-Met expression was detected in all RCC subtypes than in the adjacent normal renal tissue (P < 0.0001). Expression was highest in papillary and sarcomatoid subtypes, and high-grade and stage tumors. Higher c-Met expression correlated with worse disease-specific survival [risk ratio = 1.36; 95% confidence interval (CI) 1.08-1.74; P = 0.0091] and was an independent predictor of survival, maintained in clear cell subset analyses. c-Met protein was activated in all cell lines, and proliferation (and colony formation) was blocked by SU11274 and ARQ 197.
c-Met is associated with poor pathologic features and prognosis in RCC. c-Met inhibition demonstrates in vitro activity against clear cell RCC. Further study of ARQ 197 with appropriate biomarker studies in RCC is warranted.
Annals of oncology : official journal of the European Society for Medical Oncology. 2019 Dec 04 [Epub]
G T Gibney, S A Aziz, R L Camp, P Conrad, B E Schwartz, C R Chen, W K Kelly, H M Kluger
Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa. Electronic address: ., Section of Medical Oncology, Yale Cancer Center., Department of Pathology, Yale University School of Medicine, New Haven., Clinical Development, ArQule, Inc., Woburn., Departments of Medical Oncology and Urology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, USA.