Abstract LB-109: Identification of anaplastic lymphoma kinase fusions in clear cell renal cell carcinoma

Abstract

Abstract As the most common type of renal cancer, clear cell renal cell carcinoma (ccRCC) with advanced stages constitutes a continued major challenge for uro-oncologists where identification of novel driver mutations and development of novel targeted therapies against them remain an unmet need. Aberrations of the anaplastic lymphoma kinase (ALK) gene have been implicated in the pathogenesis of multiple human cancers where ALK represents a rational therapeutic target as demonstrated in lung cancer with ALK rearrangement. In this study, we performed the screening of ALK expression in 87 pathologically defined ccRCC by immunohistochemistry (IHC) using a newly developed rabbit anti-human ALK monoclonal antibody (clones D5F3). Four patients were positive for ALK expression as determined by IHC among which 2 cases were further confirmed by fluorescence in situ hybridization (FISH) assay using the Vysis LSI ALK dual color break-apart probe; furthermore, we detected the presence of EML4-ALK (E13:A20, variant 1) fusion gene in tumors from these two patients by using RACE-coupled PCR sequencing and RT-PCR. Notably, we first showed that enforced EML4-ALK expression significantly promoted the in vitro proliferation, clonogenic colony formation and apoptosis resistance in immortalized normal renal tubal epithelial cell HK2 and their in vivo outgrowth when injected into immunocompromised nude mice, and importantly, this pro-tumorigenic effect could be completely abolished by ALK-specific inhibitor Crizotinib, indicating the potential effectiveness of ALK-specific inhibitors in treating ALK-positive ccRCC patients. Our data show that ALK fusions exist in adult ccRCC, which provides the rationale for ALK inhibitor therapy in selected patients of ccRCC. Citation Format: Huafeng Wei, Yang Chen. Identification of anaplastic lymphoma kinase fusions in clear cell renal cell carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-109.