title: Mutant ras elevates dependence on serum lipids and creates a synthetic lethality for rapamycin.
abstract: The conversion of normal cells to cancer cells involves a shift from catabolic to anabolic metabolism involving increased glucose uptake and the diversion of glycolytic intermediates into nucleotides, amino acids, and lipids needed for cell growth. An underappreciated aspect of nutrient uptake is the utilization of serum lipids. We investigated the dependence of human cancer cells on serum lipids and report here that Ras-driven human cancer cells are uniquely dependent on serum lipids for both proliferation and survival. Removal of serum lipids also sensitizes Ras-driven cancer cells to rapamycin-indicating that the enhanced need for serum lipids creates a synthetic lethal phenotype that could be exploited therapeutically. Although depriving humans of serum lipids is not practical, suppressing uptake of lipids is possible. Suppressing macropinocytosis in Ras-driven cancer cells also created sensitivity to suppression of the mammalian/mechanistic target of rapamycin complex 1 (mTORC1). It is speculated that this property displayed by Ras-driven cancer cells represents an Achilles' heel for the large number of human cancers that are driven by activating Ras mutations.
authors.affiliation: Corresponding Author: David A. Foster, Department of Biological Sciences, Hunter College of the City University of New York, 695 Park Avenue, New York, NY 10065. foster@genectr.hunter.cuny.edu.
authors.forename: Darin
authors.initials: D
authors.lastname: Salloum
authors.forename: Suman
authors.initials: S
authors.lastname: Mukhopadhyay
authors.forename: Kaity
authors.initials: K
authors.lastname: Tung
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Polonetskaya
authors.forename: David A
authors.initials: DA
authors.lastname: Foster
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000235:genetics*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D008055:Lipids / Q000008:administration & dosage / Q000097:blood / Q000235:genetics*; D061986:MCF-7 Cells; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes / Q000235:genetics*; D009154:Mutation; D058570:TOR Serine-Threonine Kinases / Q000235:genetics*; D018631:ras Proteins / Q000097:blood / Q000235:genetics*
chemical_list: D008055:Lipids; D046912:Multiprotein Complexes; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D018631:ras Proteins