Abstract：
: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 MoA for the anticancer compounds RITA, aminoflavone (AF), and oncrasin-1 (Onc-1). Global thermal proteome profiling 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, TGFβ, and PI3K signaling pathways. Increased reactive oxygen species 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.Significance: These findings highlight agents that target transcriptional addiction in cancer cells and suggest combination treatments that target RNA processing and DNA repair pathways simultaneously as effective cancer therapies.
journal_name
Cancer Resjournal_title
Cancer researchauthors
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 Gdoi
10.1158/0008-5472.CAN-19-2069subject
Has Abstractpub_date
2020-04-01 00:00:00pages
1538-1550issue
7eissn
0008-5472issn
1538-7445pii
0008-5472.CAN-19-2069journal_volume
80pub_type
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