msb.20167321.pdf (3.16 MB)
De novo MYC addiction as an adaptive response of cancer cells to CDK4/6 inhibition
journal contributionposted on 2020-10-15, 08:44 authored by Míriam Tarrado-Castellarnau, Pedro de Atauri, Josep Tarragó-Celada, Jordi Perarnau, Mariia Yuneva, Timothy M Thomson, Marta Cascante
Cyclin-dependent kinases (CDK) are rational cancer therapeutic targets fraught with the development of acquired resistance by tumor cells. Through metabolic and transcriptomic analyses, we show that the inhibition of CDK4/6 leads to a metabolic reprogramming associated with gene networks orchestrated by the MYC transcription factor. Upon inhibition of CDK4/6, an accumulation of MYC protein ensues which explains an increased glutamine metabolism, activation of the mTOR pathway and blunting of HIF-1α-mediated responses to hypoxia. These MYC-driven adaptations to CDK4/6 inhibition render cancer cells highly sensitive to inhibitors of MYC, glutaminase or mTOR and to hypoxia, demonstrating that metabolic adaptations to antiproliferative drugs unveil new vulnerabilities that can be exploited to overcome acquired drug tolerance and resistance by cancer cells.
MYC13C metabolic flux analysisCDK4/6glutaminasetumor metabolic reprogrammingCell Line, TumorCyclin-Dependent Kinase 4Cyclin-Dependent Kinase 6Gene Expression ProfilingGene Expression Regulation, NeoplasticGene Regulatory NetworksGlutamineHCT116 CellsHumansHypoxia-Inducible Factor 1, alpha SubunitMCF-7 CellsMetabolomicsNeoplasmsPiperazinesProtein Kinase InhibitorsProto-Oncogene Proteins c-mycPyridinesTOR Serine-Threonine KinasesYuneva FC001223Bioinformatics0699 Other Biological Sciences0601 Biochemistry and Cell Biology