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Double PIK3CA mutations in cis increase oncogenicity and sensitivity to PI3Kα inhibitors
Ist Teil von
Science (American Association for the Advancement of Science), 2019-11, Vol.366 (6466), p.714-723
Ort / Verlag
United States: The American Association for the Advancement of Science
Erscheinungsjahr
2019
Link zum Volltext
Quelle
Science Online_科学在线
Beschreibungen/Notizen
Activating mutations in
are frequent in human breast cancer, and phosphoinositide 3-kinase alpha (PI3Kα) inhibitors have been approved for therapy. To characterize determinants of sensitivity to these agents, we analyzed
-mutant cancer genomes and observed the presence of multiple
mutations in 12 to 15% of breast cancers and other tumor types, most of which (95%) are double mutations. Double
mutations are in cis on the same allele and result in increased PI3K activity, enhanced downstream signaling, increased cell proliferation, and tumor growth. The biochemical mechanisms of dual mutations include increased disruption of p110α binding to the inhibitory subunit p85α, which relieves its catalytic inhibition, and increased p110α membrane lipid binding. Double
mutations predict increased sensitivity to PI3Kα inhibitors compared with single-hotspot mutations.