title: Suppression of proinvasive RGS4 by mTOR inhibition optimizes glioma treatment.
abstract: An essential mode of acquired resistance to radiotherapy (RT) appears to be promotion of tumor cell motility and invasiveness in various cancer types, including glioblastoma, a process resembling 'evasive resistance'. Hence, a logical advancement of RT would be to identify suitable complementary treatment strategies, ideally targeting cell motility. Here we report that the combination of focal RT and mammalian target of rapamycin (mTOR) inhibition using clinically relevant concentrations of temsirolimus (CCI-779) prolongs survival in a syngeneic mouse glioma model through additive cytostatic effects. In vitro, the mTOR inhibitor CCI-779 exerted marked anti-invasive effects, irrespective of the phosphatase and tensin homolog deleted on chromosome 10 status and counteracted the proinvasive effect of sublethal irradiation. Mechanistically, we identified regulator of G-protein signaling 4 (RGS4) as a novel target of mTOR inhibition and a key driver of glioblastoma invasiveness, sensitive to the anti-invasive properties of CCI-779. Notably, suppression of RGS4-dependent glioma cell invasion was signaled through both mTOR complexes, mTORC1 and mTORC2, in a concentration-dependent manner, indicating that high doses of CCI-779 may overcome tumor-cell resistance associated with the sole inhibition of mTORC1. We conclude that combined RT and mTOR inhibition is a promising therapeutic option that warrants further clinical investigation in upfront glioblastoma therapy.
authors.affiliation: Clinical Cooperation Unit Neurooncology, German Cancer Research Center DKFZ, Heidelberg, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Weiler
authors.forename: P-N
authors.initials: PN
authors.lastname: Pfenning
authors.forename: A-L
authors.initials: AL
authors.lastname: Thiepold
authors.forename: J
authors.initials: J
authors.lastname: Blaes
authors.forename: L
authors.initials: L
authors.lastname: Jestaedt
authors.forename: J
authors.initials: J
authors.lastname: Gronych
authors.forename: L M
authors.initials: LM
authors.lastname: Dittmann
authors.forename: B
authors.initials: B
authors.lastname: Berger
authors.forename: M
authors.initials: M
authors.lastname: Jugold
authors.forename: M
authors.initials: M
authors.lastname: Kosch
authors.forename: S E
authors.initials: SE
authors.lastname: Combs
authors.forename: A
authors.initials: A
authors.lastname: von Deimling
authors.forename: M
authors.initials: M
authors.lastname: Weller
authors.forename: M
authors.initials: M
authors.lastname: Bendszus
authors.forename: M
authors.initials: M
authors.lastname: Platten
authors.forename: W
authors.initials: W
authors.lastname: Wick
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D001254:Astrocytoma / Q000188:drug therapy / Q000532:radiotherapy; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy; D006801:Humans; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008875:Middle Aged; D009361:Neoplasm Invasiveness / Q000517:prevention & control; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D020710:RGS Proteins / Q000378:metabolism*; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*
chemical_list: D047428:Protein Kinase Inhibitors; D020710:RGS Proteins; C098799:RGS4 protein; C401859:temsirolimus; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus