title: Transcriptional analysis of the Aurora inhibitor Danusertib leading to biomarker identification in TP53 wild type cells.
abstract: Aurora kinases represent an appealing target for anticancer therapies and several Aurora inhibitors are in clinical development, including the potent pan-Aurora inhibitor Danusertib. Treatment with Aurora inhibitors has been shown to induce diverse biological responses in different tumor cells, in part depending on TP53 status. To characterize the effects of Danusertib at the transcriptional level we carried out gene expression profiling of wt and TP53 mutant tumor cells showing differential cell cycle response upon drug treatment. We found that treatment with Danusertib induces a strong transcriptional response only in TP53 wt cells, with an overlapping pattern of expression of TP53-dependent genes among the three cell lines tested, while a prevalent signature could not be identified in the two TP53 mutant cells, suggesting that TP53 status is a key determinant for the observed transcriptional effects. This work led to the identification of a number of genes consistently modulated by Aurora treatment in TP53 cells. One of these is GDF15, a secreted protein belonging to the TGF-β superfamily, for which we found a potential role in resistance to Danusertib, and which could represent a potential biomarker for Danusertib treatment in TP53 WT tumors and in surrogate tissues such as blood or skin.
authors.affiliation: Business Unit Oncology, Nerviano Medical Sciences srl, Nerviano (MI), Italy. roberta.bosotti@nervianoms.com
authors.forename: Roberta
authors.initials: R
authors.lastname: Bosotti
authors.forename: Patrizia
authors.initials: P
authors.lastname: Carpinelli
authors.forename: Sandra
authors.initials: S
authors.lastname: Healy
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Locatelli
authors.forename: Paolo
authors.initials: P
authors.lastname: Cappella
authors.forename: Luisa
authors.initials: L
authors.lastname: Lanfrancone
authors.forename: Raffaele
authors.initials: R
authors.lastname: Calogero
authors.forename: Jurgen
authors.initials: J
authors.lastname: Moll
authors.forename: Antonella
authors.initials: A
authors.lastname: Isacchi
mesh_terms: D064127:Aurora Kinases; D001549:Benzamides / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D002460:Cell Line; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D020869:Gene Expression Profiling; D016158:Genes, p53 / Q000502:physiology*; D005819:Genetic Markers; D006801:Humans; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011720:Pyrazoles / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D001549:Benzamides; D005819:Genetic Markers; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases; C523797:danusertib