Mutations in the oncogene NRAS that induce constitutive RAS-GTPase activity lead to unchecked cell proliferation and migration through downstream activation of the mitogen-activated protein kinase(MAPK)and phosphoinos...Mutations in the oncogene NRAS that induce constitutive RAS-GTPase activity lead to unchecked cell proliferation and migration through downstream activation of the mitogen-activated protein kinase(MAPK)and phosphoinositide 3-kinase(PI3K)signalling pathways[1].These mutations occur in approximately 20%of melanomas and very rarely coexist with BRAF V600 mutations.NRASmutant melanoma is associated with poor survival[2]and represents an unmet clinical need,with no effective therapies available following immunotherapy failure.Identification of contextual essential genes that exert stronger fitness effects on NRAS-mutant melanoma cells presents an opportunity for the discovery of targeted therapies.In this study,we employed CRISPR-Cas9-mediated whole-genome dropout screens to identify genetic dependencies in NRAS-mutant melanoma.Typically,melanoma cell lines are cultured under ambient(∼20%)O_(2) conditions,despite O_(2 )concentrations of<8%at the epidermaldermal junction where melanocytes reside,resulting in adaptations in gene and protein expression[3].展开更多
基金funded by the Cancer Society of New Zealand(18.14)Cancer Research Trust New Zealand(2005-PGS)University of Auckland Genomics into Medicine Strategic Research Initiatives Fund and Maurice Wilkins Centre for Molecular Biodiscovery Flexible Research Programme.
文摘Mutations in the oncogene NRAS that induce constitutive RAS-GTPase activity lead to unchecked cell proliferation and migration through downstream activation of the mitogen-activated protein kinase(MAPK)and phosphoinositide 3-kinase(PI3K)signalling pathways[1].These mutations occur in approximately 20%of melanomas and very rarely coexist with BRAF V600 mutations.NRASmutant melanoma is associated with poor survival[2]and represents an unmet clinical need,with no effective therapies available following immunotherapy failure.Identification of contextual essential genes that exert stronger fitness effects on NRAS-mutant melanoma cells presents an opportunity for the discovery of targeted therapies.In this study,we employed CRISPR-Cas9-mediated whole-genome dropout screens to identify genetic dependencies in NRAS-mutant melanoma.Typically,melanoma cell lines are cultured under ambient(∼20%)O_(2) conditions,despite O_(2 )concentrations of<8%at the epidermaldermal junction where melanocytes reside,resulting in adaptations in gene and protein expression[3].
