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posted on 2024-07-01, 07:41 authored by Matheus Henrique Dias, Anoek Friskes, Siying Wang, Joao M. Fernandes Neto, Frank van Gemert, Soufiane Mourragui, Chrysa Papagianni, Hendrik J. Kuiken, Sara Mainardi, Daniel Alvarez-Villanueva, Cor Lieftink, Ben Morris, Anna Dekker, Emma van Dijk, Lieke H.S. Wilms, Marcelo S. da Silva, Robin A. Jansen, Antonio Mulero-Sánchez, Elke Malzer, August Vidal, Cristina Santos, Ramón Salazar, Rosangela A.M. Wailemann, Thompson E.P. Torres, Giulia De Conti, Jonne A. Raaijmakers, Petur Snaebjornsson, Shengxian Yuan, Wenxin Qin, John S. Kovach, Hugo A. Armelin, Hein te Riele, Alexander van Oudenaarden, Haojie Jin, Roderick L. Beijersbergen, Alberto Villanueva, Rene H. Medema, Rene Bernards Figure S4: Combined toxicity of LB-100 and Adavosertib in CRC models (A) Dose-response assays show the effect of Adavosertib in 7 CRC models. Cell viability was estimated by resazurin fluorescence after 5 days in the presence of the drug or DMSO control. The normalized values are plotted. (B) Long-term viability assays show 7 CRC models treated with LB-100 or Adavosertib at the indicated concentrations. Treatments were refreshed every 2-3 days, and the cells were grown for 10-14 days before fixing, staining, and imaging. (C) IncuCyte-based proliferation assays from 7 CRC models in the absence or presence of LB-100, Adavosertib, or the combination at the indicated concentrations. (D) Dose-response assays show the toxicity of LB-100 and Adavosertib in BJ and HaCaT cells compared to the average across the 7 CRC cell lines listed in the supplementary table S1. Cell viability was estimated by resazurin fluorescence after 5 days in the presence of the drug or DMSO control. The normalized values are plotted. (E) Synergy matrices and scores for the combination of LB-100 and Adavosertib in BJ and HaCaT cells. Cells were treated with 5 concentrations of LB-100 (1, 2, 3, 4, and 5 µM) or Adavosertib (100, 200, 300, 400, and 500 nM) and all respective permutations for 4 days. The percentage of cell viability for each condition was estimated by resazurin fluorescence and normalized to DMSO controls. Synergyfinder.org web tool was used to calculate the ZIP synergy scores and generate the plots.
Funding
Sao Paolo Research Foundation
Shanghai Academic/Technology Research Leader
Instituto de Salud Carlos III
CERCA Program/Generalitat de Catalunya
São Paulo State Foundation-FAPESP: CeTICS-Grant
European Research Council (ERC)
Instituto de Salud Carlos III (ISCIII)
National Natural Science Foundation of China (NSFC)
History
ARTICLE ABSTRACT
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 suppressed the growth of patient-derived tumors in vivo. Remarkably, acquired resistance to this drug combination suppressed the ability of colon cancer cells to form tumors in vivo. Our data suggest that paradoxical activation of oncogenic signaling can result in tumor-suppressive resistance.Significance: A therapy consisting of deliberate hyperactivation of oncogenic signaling combined with perturbation of the stress responses that result from this is very effective in animal models of colon cancer. Resistance to this therapy is associated with loss of oncogenic signaling and reduced oncogenic capacity, indicative of tumor-suppressive drug resistance.
