title: ABCG2 impairs the activity of the aurora kinase inhibitor tozasertib but not of alisertib.
abstract: BACKGROUND
  Recently, we have shown that the ATP-binding cassette (ABC) transporter ABCB1 interferes with the anti-cancer activity of the pan-aurora kinase inhibitor tozasertib (VX680, MK-0457) but not of the aurora kinase A and B inhibitor alisertib (MLN8237). Preliminary data had suggested tozasertib also to be a substrate of the ABC transporter ABCG2, another ABC transporter potentially involved in cancer cell drug resistance. Here, we studied the effect of ABCG2 on the activity of tozasertib and alisertib.
  
  
  RESULTS
  The tozasertib concentration that reduces cell viability by 50% (IC50) was dramatically increased in ABCG2-transduced UKF-NB-3(ABCG2) cells (48.8-fold) compared to UKF-NB-3 cells and vector-transduced control cells. The ABCG2 inhibitor WK-X-34 reduced tozasertib IC50 to the level of non-ABCG2-expressing UKF-NB-3 cells. Furthermore, ABCG2 depletion from UKF-NB-3(ABCG2) cells using another lentiviral vector expressing an shRNA against the bicistronic mRNA of ABCG2 and eGFP largely re-sensitised these cells to tozasertib. In contrast, alisertib activity was not affected by ABCG2 expression.
  
  
  CONCLUSIONS
  Tozasertib but not alisertib activity is affected by ABCG2 expression. This should be considered within the design and analysis of experiments and clinical trials investigating these compounds.
authors.affiliation: Institut für Medizinische Virologie, Klinikum der Goethe-Universität, Paul Ehrlich-Str. 40, 60596, Frankfurt Am Main, Germany. M.Michaelis@kent.ac.uk.|Centre for Molecular Processing and School of Biosciences, University of Kent, Canterbury, CT2 7NJ, UK. M.Michaelis@kent.ac.uk.
authors.forename: Martin
authors.initials: M
authors.lastname: Michaelis
authors.affiliation: Institut für Medizinische Virologie, Klinikum der Goethe-Universität, Paul Ehrlich-Str. 40, 60596, Frankfurt Am Main, Germany. f.selt@dkfz.de.|Deutsches Krebsforschungszentrum (DKFZ), Klinische Kooperationseinheit Pädiatrische Onkologie (G340) and Pädiatrie III, Zentrum für Kinder- und Jugendmedizin, Im Neuenheimer Feld 280, 69120, Heidelberg, Germany. f.selt@dkfz.de.
authors.forename: Florian
authors.initials: F
authors.lastname: Selt
authors.affiliation: Institut für Medizinische Virologie, Klinikum der Goethe-Universität, Paul Ehrlich-Str. 40, 60596, Frankfurt Am Main, Germany. f.rothweiler@kinderkrebsstiftung-frankfurt.de.
authors.forename: Florian
authors.initials: F
authors.lastname: Rothweiler
authors.affiliation: Pharmaceutical Institute, University of Bonn, An der Immenburg 4, 53121, Bonn, Germany. mwiese@uni-bonn.de.
authors.forename: Michael
authors.initials: M
authors.lastname: Wiese
authors.affiliation: Institut für Medizinische Virologie, Klinikum der Goethe-Universität, Paul Ehrlich-Str. 40, 60596, Frankfurt Am Main, Germany. Cinatl@em.uni-frankfurt.de.
authors.forename: Jindrich
authors.initials: J
authors.lastname: Cinatl
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D064127:Aurora Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001381:Azepines / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D009363:Neoplasm Proteins / Q000378:metabolism*; D010879:Piperazines / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D016896:Treatment Outcome; D003521:Cyclopropanes; D011720:Pyrazoles
chemical_list: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D064127:Aurora Kinases; D001381:Azepines; D009363:Neoplasm Proteins; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; C116614:ABCG2 protein, human; C550258:MLN 8237; C484810:tozasertib; D003521:Cyclopropanes; D011720:Pyrazoles