c-Met expression in renal cell carcinoma with bone metastases

Abstract

Hepatocyte growth factor (HGF)/c-Met pathway is implicated in embryogenesis and organ development and differentiation. Germline or somatic mutations, chromosomal rearrangements, gene amplification, and transcriptional upregulation in MET or alterations in autocrine or paracrine c-Met signalling have been associated with cancer cell proliferation and survival, including in renal cell carcinoma (RCC), and associated with disease progression. HGF/c-Met pathway has been shown to be particularly relevant in tumors with bone metastases (BMs). However, the efficacy of targeting c-Met in bone metastatic disease, including in RCC, has not been proven. Therefore, further investigation is required focusing the particular role of HGF/c-Met pathway in bone microenvironment (BME) and how to effectively target this pathway in the context of bone metastatic disease.

Keywords: ALK, anaplastic lymphoma kinase gene; AR, androgen receptor; ATP, adenosine triphosphate; AXL, AXL Receptor Tyrosine Kinase; BME, bone microenvironment; BMPs, bone morphogenetic proteins; BMs, bone metastases; BPs, Bisphosphonates; BTAs, Bone-targeting agents; Bone metastases; CCL20, chemokine (C-C motif) ligand 20; CI, confidence interval; CRPC, Castration Resistant Prostate Cancer; CSC, cancer stem cells; CTC, circulating tumor cells; CaSR, calcium/calcium-sensing receptor; EMA, European Medicines Agency; EMT, epithelial-to-mesenchymal transition; FDA, US Food and Drug Administration; FLT-3, FMS-like tyrosine kinase 3; GEJ, Gastroesophageal Junction; HCC, Hepatocellular Carcinoma; HGF, hepatocyte growth factor; HGF/c-Met; HIF, hypoxia-inducible factors; HR, hazard ratio; IGF, insulin-like growth factor; IGF2BP3, insulin mRNA Binding Protein-3; IL, interleukin; IRC, independent review committees; KIT, tyrosine-protein kinase KIT; Kidney cancer; M-CSF, macrophage colony-stimulating factor; MET, MET proto-oncogene, receptor tyrosine kinase; NSCLC, non-small cell lung carcinoma; ORR, overall response rate; OS, overall survival; PDGF, platelet-derived growth factor; PFS, progression free survival; PTHrP, parathyroid hormone-related peptide; RANKL, receptor activator of nuclear factor-κB ligand; RCC, renal cell carcinoma; RET, rearranged during transfection proto-oncogene; ROS, proto-oncogene tyrosine-protein kinase ROS; RTK, receptor tyrosine kinase; SCLC, Squamous Cell Lung Cancer; SREs, skeletal-related events; SSE, symptomatic skeletal events; TGF-β, transforming growth factor-β; TIE-2, Tyrosine-Protein Kinase Receptor TIE-2; TKI, tyrosine kinase inhibitor; TRKB, Tropomyosin receptor kinase B; Targeted therapy; VEGFR, vascular endothelial growth factor receptor; VHL, Hippel-Lindau tumor suppressor gene; ZA, zoledronic acid; ccRCC, clear-cell RCC; mAb, monoclonal antibodies; pRCC, papillary renal cell carcinoma.