Paradoxical 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...

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Vydané v:	Cancer discovery Ročník 14; číslo 7; s. 1276
Hlavní autori:	Dias, Matheus Henrique, Friskes, Anoek, Wang, Siying, Fernandes Neto, Joao M, van Gemert, Frank, Mourragui, Soufiane, Papagianni, Chrysa, Kuiken, Hendrik J, Mainardi, Sara, Alvarez-Villanueva, Daniel, Lieftink, Cor, Morris, Ben, Dekker, Anna, van Dijk, Emma, Wilms, Lieke H S, da Silva, Marcelo S, Jansen, Robin A, Mulero-Sánchez, Antonio, Malzer, Elke, Vidal, August, Santos, Cristina, Salazar, Ramón, Wailemann, Rosangela A M, Torres, Thompson E P, De Conti, Giulia, Raaijmakers, Jonne A, Snaebjornsson, Petur, Yuan, Shengxian, Qin, Wenxin, Kovach, John S, Armelin, Hugo A, Te Riele, Hein, van Oudenaarden, Alexander, Jin, Haojie, Beijersbergen, Roderick L, Villanueva, Alberto, Medema, Rene H, Bernards, Rene
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	United States 01.07.2024
Predmet:	Animals Cell Cycle Proteins - antagonists & inhibitors Cell Cycle Proteins - metabolism Cell Line, Tumor Colonic Neoplasms - drug therapy Colonic Neoplasms - genetics Colonic Neoplasms - metabolism Colonic Neoplasms - pathology DNA Replication Drug Resistance, Neoplasm Humans Mice Nuclear Proteins - genetics Nuclear Proteins - metabolism Protein Phosphatase 2 - metabolism Protein-Tyrosine Kinases - antagonists & inhibitors Protein-Tyrosine Kinases - metabolism Signal Transduction Xenograft Model Antitumor Assays
ISSN:	2159-8290, 2159-8290
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Shrnutí:	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.
Bibliografia:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2159-8290 2159-8290
DOI:	10.1158/2159-8290.CD-23-0216