title: Inhibition of Galectin-1 Sensitizes HRAS-driven Tumor Growth to Rapamycin Treatment.
abstract: The goal of this study was to develop combinatorial application of two drugs currently either in active use as anticancer agents (rapamycin) or in clinical trials (OTX008) as a novel strategy to inhibit Harvey RAS (HRAS)-driven tumor progression. HRAS anchored to the plasma membrane shuttles from the lipid ordered (Lo) domain to the lipid ordered/lipid disordered border upon activation, and retention of HRAS at these sites requires galectin-1. We recently showed that genetically enforced Losequestration of HRAS inhibited mitogen-activated protein kinase (MAPK) signaling, but not phoshatidylinositol 3-kinase (PI3K) activation. Here we show that inhibition of galectin-1 with OTX008 sequestered HRAS in the Lodomain, blocked HRAS-mediated MAPK signaling, and attenuated HRAS-driven tumor progression in mice. HRAS-driven tumor growth was also attenuated by treatment with mammalian target of rapamycin (mTOR) inhibitor rapamycin, and this effect was further enhanced in tumors driven by Lo-sequestered HRAS. These drugs also revealed bidirectional cross-talk in HRAS pathways. Moreover, dual pathway inhibition with OTX008 and rapamycin resulted in nearly complete ablation of HRAS-driven tumor growth. These findings indicate that membrane microdomain sequestration of HRAS with galectin-1 inhibition, coupled with mTOR inhibition, may support a novel therapeutic approach to treat HRAS-mutant cancer.
authors: Department of Anatomy and Cell Biology, The Sol Sherry Thrombosis Research Center, Temple University School of Medicine, Philadelphia, PA, U.S.A.
authors: James V
authors: JV
authors: Michael
authors: Department of Anatomy and Cell Biology, The Sol Sherry Thrombosis Research Center, Temple University School of Medicine, Philadelphia, PA, U.S.A.
authors: Jeremy G T
authors: JG
authors: Wurtzel
authors: Department of Anatomy and Cell Biology, The Sol Sherry Thrombosis Research Center, Temple University School of Medicine, Philadelphia, PA, U.S.A. goldfinger@temple.edu.|Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA, U.S.A.
authors: Lawrence E
authors: LE
authors: Goldfinger
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D047250:Calixarenes / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D037483:Galectin 1 / Q000037:antagonists & inhibitors*; D049452:Green Fluorescent Proteins / Q000235:genetics; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008819:Mice, Nude; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors / Q000378:metabolism; D041681:NIH 3T3 Cells; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism*; D020123:Sirolimus / Q000494:pharmacology* / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D037483:Galectin 1; D046912:Multiprotein Complexes; C530377:compound 0118; D047250:Calixarenes; D049452:Green Fluorescent Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D020928:Mitogen-Activated Protein Kinases; D016283:Proto-Oncogene Proteins p21(ras); D020123:Sirolimus
keywords: ERK; RAS; dual inhibition; galectin; mTOR; rapamycin