Peuget S, Zhu J, Sanz G, Singh M, Gaetani M, Chen X, Shi Y, Saei AA, Visnes T, Lindström MS, Rihani A, Moyano-Galceran L, Carlson JW, Hjerpe E, Joneborg U, Lehti K, Hartman J, Helleday T, Zubarev R, Selivanova G
Cancer Res - (-) canres.2069.2019 [2020-02-04; online 2020-02-04]
Identification of the molecular mechanism of action (MoA) of bioactive compounds is a crucial step for drug development but remains a challenging task despite recent advances in technology. In this study, we applied multidimensional proteomics, sensitivity correlation analysis and transcriptomics to identify a common mechanism of action for the anticancer compounds RITA, aminoflavone (AF) and oncrasin-1 (Onc-1). Global thermal proteome profiling (TPP) revealed that the three compounds target mRNA processing and transcription, thereby attacking a cancer vulnerability - transcriptional addiction. This led to the preferential loss of expression of oncogenes involved in PDGF-, EGFR-, VEGF-, Insulin/IGF/MAPKK-, FGF-, Hedgehog-, TGF-beta- and PI3K-signaling pathways. Increased reactive oxygen species (ROS) level in cancer cells was a prerequisite for targeting the mRNA transcription machinery, thus conferring cancer-selectivity to these compounds. Furthermore, DNA repair factors involved in homologous recombination were among the most prominently repressed proteins. In cancer patient samples, RITA, AF and Onc-1 sensitized to poly(ADP-ribose) polymerase inhibitors both in vitro and ex vivo. These findings might pave a way for new synthetic lethal combination therapies.
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