biostudies-literatureDias MHCERCA Program/Generalitat de CatalunyaEuropean Research CouncilInstituto de Salud Carlos IIISao Paolo Research FoundationShanghai Academic/Technology Research LeaderNational Natural Science Foundation of ChinaInstituto de Salud Carlos III (ISCIII)National Natural Science Foundation of China (NSFC)São Paulo State Foundation-FAPESP: CeTICS-Grant1276-1301https://www.ebi.ac.uk/biostudies/studies/S-EPMC11215412biostudies-literatureUnknown14(7)Cancer homeostasis depends on a balance between activated oncogenic pathways driving tumorigenesis and engagement of stress response programs that counteract the inherent toxicity of such aberrant signaling. Although inhibition of oncogenic signaling pathways has been explored extensively, there is increasing evidence that overactivation of the same pathways can also disrupt cancer homeostasis and cause lethality. We show here that inhibition of protein phosphatase 2A (PP2A) hyperactivates multiple oncogenic pathways and engages stress responses in colon cancer cells. Genetic and compound screens identify combined inhibition of PP2A and WEE1 as synergistic in multiple cancer models by collapsing DNA replication and triggering premature mitosis followed by cell death. This combination also Cancer discoveryParadoxical Activation of Oncogenic Signaling as a Cancer Treatment Strategy.PMC11215412PI19-01320 and PI22-005482019/10753-22013/07467-12017SGR449 and 2021 SGR 001842020/10277-3FI20/00130grant 8222204778792522XD1423100Morris BDekker AMedema RHMainardi SQin WArmelin HAMulero-Sanchez ALieftink CVidal ABernards RKuiken HJJin HBeijersbergen RLSalazar RSnaebjornsson PWang Sda Silva MSvan Oudenaarden AVillanueva AFriskes AYuan SKovach JSDias MHPapagianni CWailemann RAMTorres TEPDe Conti GJansen RATe Riele HAlvarez-Villanueva Dvan Gemert FRaaijmakers JASantos CWilms LHSFernandes Neto JMvan Dijk EMourragui SMalzer EfalseParadoxical Activation of Oncogenic Signaling as a Cancer Treatment Strategy.Cancer homeostasis depends on a balance between activated oncogenic pathways driving tumorigenesis and engagement of stress response programs that counteract the inherent toxicity of such aberrant signaling. Although inhibition of oncogenic signaling pathways has been explored extensively, there is increasing evidence that overactivation of the same pathways can also disrupt cancer homeostasis and cause lethality. We show here that inhibition of protein phosphatase 2A (PP2A) hyperactivates multiple oncogenic pathways and engages stress responses in colon cancer cells. Genetic and compound screens identify combined inhibition of PP2A and WEE1 as synergistic in multiple cancer models by collapsing DNA replication and triggering premature mitosis followed by cell death. This combination also 2024-01-01T00:00:00Z2024 Jul2026-06-26T03:11:12.814Z2025-04-07T02:11:21.789ZS-EPMC112154123853398710.1158/2159-8290.CD-23-0216