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Baseline 2 weeks Molecular Cancer Therapeutics Highlights January 2018 * Volume 17 * Number 1 Selected Articles from This Issue Targeting ALK in melanoma Couts et al. Page 222 Anaplastic lymphoma kinase (ALK) is an oncogenic kinase which can be expressed and activated in cancers by gene fusions. ALK fusions have not been identified in cutaneous melanomas, but expression of an alternate isoform of ALK (ALK ATI ) was reported as a potential therapeutic target in 10% of melanomas. In this study, Couts and colleagues identified an EML4-ALK fusion in a non-cutaneous mucosal melanoma and show it is highly sensitive to ALK inhibitors, whereas melanomas expressing ALK ATI do not respond. These results highlight ALK fusions as a new therapeutic target in non-cutaneous melanomas and suggest ALK ATI may have limited clinical utility. Dual inhibition of HDAC and MEK in RAS lung cancers Yamada et al. Page 17 An effective therapeutic strategy has yet to be developed for non-small-cell lung cancer patients with KRAS mutations. Here, Yamada and colleagues show that a combination of MEK and histone deacetylase inhibitors can be effective in KRAS mutant lung cancer cell lines. The mechanism was shown to be through the increase in FOXO protein levels and transcriptional activity. FOXO proteins are known to regulate proteins involved in apoptosis. These results demonstrate that control of FOXOs localization and expression is critical in RAS driven lung cancer cells, suggesting that the dual molecular targeted therapy for MEK and HDACs may be promising as novel therapeutic strategy in RAS mutated lung cancer. Menin-MLL inhibition in hepatocellular carcinoma Kempinska et al. Page 26 The protein-protein interaction between menin and MLL1 (Mixed Lineage Leukemia 1) plays an important role in the development of hepatocellular carcinoma (HCC). Here, Kempinska and colleagues demonstrate that the menin-MLL1 inhibitor MI-503 shows pronounced anti- tumor activity in in vitro and in vivo models of HCC, both as a single agent and in combination with sorafenib. Studies with MI-503 also reveal the potential mechanism of menin activity in HCC demonstrating that menin regulates the expression of genes critical to proliferation and migration of HCC cells, including PEG10. These results might lead to new therapeutic strategies for HCC. HIF2a-targeted RNAi therapeutic Wong et al. Page 140 Frequent inactivation of the von Hippel- Landau protein (pVHL) and the subsequent over-expression of HIF2a have been attributed as tumorigenic drivers of clear cell renal cell carcinoma (ccRCC). Here, Wong and colleagues report the functional delivery of an RNAi- based therapeutic targeting HIF2a,a transcription factor generally regarded as undruggable, using a targeted RNAi delivery approach for ccRCC. RNAi mediated HIF2a gene silencing resulted in tumor growth inhibition and down regulation of HIF2a regulated genes that promote tumor growth. A successful first- in-class RNAi therapeutic for ccRCC will provide a much-needed alternative for treatment refractory patients expressing aVb3 or aVb5 integrins. www.aacrjournals.org 1 on July 12, 2020. © 2018 American Association for Cancer Research. mct.aacrjournals.org Downloaded from
