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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Veröffentlicht in:Cancer discovery Jg. 14; H. 7; S. 1276
Hauptverfasser: 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
Format: Journal Article
Sprache:Englisch
Veröffentlicht: United States 01.07.2024
Schlagworte:
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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Zusammenfassung: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.
Bibliographie:ObjectType-Article-1
SourceType-Scholarly Journals-1
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content type line 23
ISSN:2159-8290
2159-8290
DOI:10.1158/2159-8290.CD-23-0216