Abstract
ABSTRACTOncogenic Ras mutations are highly prevalent in hematopoietic malignancies. However, it is difficult to directly target oncogenic RAS proteins for therapeutic intervention. We have developed a Drosophila acute myeloid leukemia model induced by human KRASG12V, which exhibits a dramatic increase in myeloid-like leukemia cells. We performed both genetic and drug screens using this model. The genetic screen identified 24 candidate genes able to attenuate the oncogenic RAS-induced phenotype, including two key hypoxia pathway genes HIF1A and ARNT (HIF1B). The drug screen revealed that echinomycin, an inhibitor of HIF1A, can effectively attenuate the leukemia phenotype caused by KRASG12V. Furthermore, we showed that echinomycin treatment can effectively suppress oncogenic RAS-driven leukemia cell proliferation, using both human leukemia cell lines and a mouse xenograft model. These data suggest that inhibiting the hypoxia pathway could be an effective treatment approach and that echinomycin is a promising targeted drug to attenuate oncogenic RAS-induced cancer phenotypes. This article has an associated First Person interview with the first author of the paper.
Highlights
Mutations of the RAS family genes, consisting of HRAS, KRAS and NRAS, are involved in over 30% of all human cancers (Downward, 2015; Pylayeva-Gupta et al, 2011)
In this study, we generated a new KRASG12V leukemia model in Drosophila by expressing human oncogenic KRASG12V in the fly hemocytes, which led to nearly 100-fold increase in hemocyte proliferation and adult fly lethality
The parallel genetic and drug screens converged on the same pathways, as they identified both the key genes involved in the hypoxia pathway, as well as the hypoxia inhibitor echinomycin as potent oncogenic KRAS antagonists
Summary
Mutations of the RAS family genes, consisting of HRAS, KRAS and NRAS, are involved in over 30% of all human cancers (Downward, 2015; Pylayeva-Gupta et al, 2011). KRAS is an especially prevalent contributor to human cancers affecting the pancreas, colon and lung (Downward, 2015; Pylayeva-Gupta et al, 2011). RAS genes encode highly conserved GTP-binding proteins involved in eukaryotic cell proliferation and differentiation (McCormick, 1994), which cycle between active GTP-bound and inactive GDP-bound states. Many oncogenic RAS mutations lock RAS in a constitutively activated state, which triggers the activation of multiple interacting signaling pathways (Bos, 1989; Downward, 2003). Invigorating the call for combinatorial strategies to optimize treatment of RAS-mediated cancers has been proposed (Hallin et al, 2020)
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