title: Killing of Kras-mutant colon cancer cells via Rac-independent actin remodeling by the βGBP cytokine, a physiological PI3K inhibitor therapeutically effective in vivo.
abstract: Activating mutations in Kras are the most frequent mutations in human cancer. They define a subset of patients who do not respond to current therapies and for whom prognosis is poor. Oncogenic Kras has been shown to deregulate numerous signaling pathways of which the most intensively studied are the Ras/extracellular signal-regulated kinase cascade and the phosphoinositide 3-kinase (PI3K)/Akt cascade. However, to date, there are no effective targeted therapies in the clinic against Kras-mutant cancers. Here, we report that the β-galactoside-binding protein (βGBP) cytokine, a physiologic inhibitor of class I PI3Ks, is a potent activator of apoptosis in Kras-mutant colorectal cancer cells, even when coharboring mutant-activated PIK3CA. Our study unveils an elective route to intrinsic and extrinsic apoptosis, which involves the cytoskeleton. Early events are inhibition of PI3K activity and Rac-independent actin rearrangement assignable to phosphoinositide changes at the plasma membrane. Cyclin E deregulation, arrest of DNA synthesis, and checkpoint kinase 2 activation underscore events critical to the activation of an intrinsic apoptotic program. Clustering of CD95/Fas death receptors underscore events critical to the activation of extrinsic apoptosis. In nude mice, we present the first evidence that xenograft tumor development is strongly inhibited by Hu-r-βGBP. Taken together, our results open a new therapeutic opportunity to a subset of patients refractive to current treatments. This first demonstration of therapeutic efficacy against Kras-mutant colon cancer suggests that Hu-r-βGBP may also be therapeutically effective against other cancers harboring activating Ras mutations as well as PIK3CA mutations.
authors: School of Biomedical and Health Sciences, King's College London, London, United Kingdom. livio.mallucci@kcl.ac.uk
authors: Livio
authors: L
authors: Mallucci
authors: Dong-yun
authors: DY
authors: Shi
authors: Derek
authors: D
authors: Davies
authors: Peter
authors: P
authors: Jordan
authors: Alastair
authors: A
authors: Nicol
authors: Lavinia
authors: L
authors: Lotti
authors: Renato
authors: R
authors: Mariani-Costantini
authors: Fabio
authors: F
authors: Verginelli
authors: Valerie
authors: V
authors: Wells
authors: Daniel
authors: D
authors: Zicha
mesh_terms: D000199:Actins / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D048430:Cell Shape; D064447:Checkpoint Kinase 2; D003110:Colonic Neoplasms / Q000188:drug therapy*; D019927:Cyclin E / Q000378:metabolism; D004261:DNA Replication; D019008:Drug Resistance, Neoplasm; D004789:Enzyme Activation; D005260:Female; D037161:Galectins / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D008819:Mice, Nude; D020125:Mutation, Missense; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D023041:Xenograft Model Antitumor Assays; D019014:fas Receptor / Q000378:metabolism; D020744:rac GTP-Binding Proteins / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics*
chemical_list: D000199:Actins; D000970:Antineoplastic Agents; D064447:Checkpoint Kinase 2; D019927:Cyclin E; D037161:Galectins; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D016283:Proto-Oncogene Proteins p21(ras); D019014:fas Receptor; D020744:rac GTP-Binding Proteins; D018631:ras Proteins; C491901:FAS protein, human; C117307:KRAS protein, human; C578634:CHEK2 protein, human; C578633:Chek2 protein, mouse