Figure S6 from Paradoxical Activation of Oncogenic Signaling as a Cancer Treatment Strategy

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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 S6: LB-100 and adavosertib induce histological response in orthotopic CRC PDXs (A) Representative Hematoxylin & Eosin (H&E) stainings at endpoint from PDOX2 and PDOX3 treated as indicated. Original magnification middle images: 15x, scale bar 1000 µm; right images: 200x. S indicates stroma, and the arrows point to the tumor-cell component. (B) Mice body weight variation of the 3 CRC PDXs across the experiments.

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)

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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.

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Keywords

Cell Signaling Phosphatases

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