Landscape of RAF1 fusions in solid tumors and therapeutic utility of sorafenib

• Published in: European journal of cancer (1990) 2016-12, Vol.69, p.S142-S142
• Main Authors: Mehnert, J, Ali, S, Kulkarni, A, Pavlick, D, Goydos, J, Chen, S, Shrock, A, Hirshfield, K, Rodriguez, L, Stein, M, White, E, Ross, J, Miller, V, Stephens, P, Ganesan, S
• Format: Article
• Language: English
• Subjects: Adenocarcinoma; Brain; Brain tumors; Breakpoints; Cancer; Cell growth; Cell survival; Fusion protein; Genes; Hematology, Oncology and Palliative Medicine; Inhibitor drugs; Inhibitors; Kinases; Lesions; Lung cancer; Lungs; Melanoma; Metastases; Mutation; Neuroendocrine tumors; Pancreatic cancer; Pancreatic carcinoma; Patients; Prostate cancer; Prostate carcinoma; Raf protein; Shrinkage; Skin; Solid tumors; Tumors
• ISSN: 0959-8049; 1879-0852
• DOI: 10.1016/S0959-8049(16)33022-2

Background: Fusions involving the RAF1 (cRAF) kinase have been reported in several solid tumors as likely driver mutations. We now present the landscape of RAF1 fusions identified through clinical grade comprehensive genomic profiling of 79,209 solid tumors. A clinical response to sorafenib in a patient with pancreatic acinar carcinoma harboring a RAF1 fusion demonsrates the potential clinical utility of the RAF inhibitor sorafenib. Methods: Data from clinical grade comprehensive genomic profiling performed on 79,209 solid tumor samples using the FoundationOne assay was reviewed to identify cases harboring RAF1 fusions. A patient with refractory pancreatic acinar cancer was referred for treatment as part of a phase I trial of sorafenib combined with a glutatmate antagonist, based on the presence of a KANK4-RAF1 fusion identified by FoundationOne assay. A cDNA encoding KANK4-RAF1 fusion was synthesized and used to express fusion gene in NIH3T3 cells; cell growth and survival was measured using colony formation. Results: 59 in-frame RAF1 fusion events were seen in 79,209 solid tumors. The most common tumor types included lung non-small cell (8 cases or which 7 were adenocarcinoma, 0.05% of all lung cancers), melanoma (9 cases, 0.5% of melanoma), skin (10 cases) pancreatic cancer (9 cases, of which 3 were pancreatic acinar carcinomas and 3 were neuroendocrine cancers), brain (8 cases), and prostate (4 cases). These fusions result from 8 unique breakpoints, almost all occurring in intron 7 of RAF1, and involved 44 unique fusion partners. An index patient with metastatic pancreatic acinar cancer refractory to standard therapy, that harbored a KANK4-RAF1 fusion, experienced dramatic clinical improvement with RECIST partial response and more than 40 per cent tumor shrinkage in target lesions when treated with sorafenib and the glutamate antagonist riluzole on an investigational trial. In vitro characterization of the KANK4-RAF1 fusion, including sensitivity to RAF kinase inhibitors will be presented. Conclusions: In this large dataset, RAF1 fusions are present in multiple solid tumor types including lung adenocarcinomas, melanomas, pancreatic acinar carcinomas and prostate cancer. Cancers harboring RAF1 fusions may be exceptionally sensitive to treatment with RAF inhibitors. We propose further clinical investigation of RAF inhibitors such as sorafenib in pancreatic acinar and other cancers with RAF1 fusions.