Baseline 2 weeks
Molecular Cancer Therapeutics
HighlightsJanuary 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 beexpressed and activated in cancers by gene fusions. ALK fusions have notbeen identified in cutaneous melanomas, but expression of an alternateisoform of ALK (ALKATI) was reported as a potential therapeutic target in10% of melanomas. In this study, Couts and colleagues identified anEML4-ALK fusion in a non-cutaneousmucosal melanoma and show it ishighly sensitive to ALK inhibitors, whereas melanomas expressingALKATI do not respond. These results highlight ALK fusions as a newtherapeutic target in non-cutaneousmelanomas and suggest ALKATI mayhave limited clinical utility.
Dual inhibition of HDACandMEK in RAS lung cancers
Yamada et al. Page 17
An effective therapeutic strategy has yet tobe developed for non-small-cell lungcancer patients with KRAS mutations.Here, Yamada and colleagues show that acombination of MEK and histonedeacetylase inhibitors can be effective inKRAS mutant lung cancer cell lines. Themechanism was shown to be through theincrease in FOXO protein levels andtranscriptional activity. FOXOproteins areknown to regulate proteins involved inapoptosis. These results demonstrate thatcontrol of FOXOs localization andexpression is critical in RAS driven lungcancer cells, suggesting that the dualmolecular targeted therapy for MEK andHDACs may be promising as noveltherapeutic strategy in RAS mutated lungcancer.
Menin-MLL inhibition inhepatocellular carcinoma
Kempinska et al. Page 26
The protein-protein interaction betweenmenin and MLL1 (Mixed LineageLeukemia 1) plays an important role in thedevelopment of hepatocellular carcinoma(HCC). Here, Kempinska and colleaguesdemonstrate that the menin-MLL1inhibitor MI-503 shows pronounced anti-tumor activity in in vitro and in vivomodelsof HCC, both as a single agent and incombination with sorafenib. Studies withMI-503 also reveal the potentialmechanism of menin activity in HCCdemonstrating that menin regulates theexpression of genes critical to proliferationand migration of HCC cells, includingPEG10. These results might lead to newtherapeutic strategies for HCC.
HIF2a-targeted RNAitherapeutic
Wong et al. Page 140
Frequent inactivation of the von Hippel-Landau protein (pVHL) and thesubsequent over-expression of HIF2ahave been attributed as tumorigenicdrivers of clear cell renal cell carcinoma(ccRCC). Here, Wong and colleaguesreport the functional delivery of an RNAi-based therapeutic targeting HIF2a, atranscription factor generally regarded asundruggable, using a targeted RNAidelivery approach for ccRCC. RNAimediatedHIF2a gene silencing resulted intumor growth inhibition and downregulation of HIF2a regulated genes thatpromote tumor growth. A successful first-in-class RNAi therapeutic for ccRCC willprovide a much-needed alternative fortreatment refractory patients expressingaVb3 or aVb5 integrins.
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