Miniatura

Fitxers

859969.pdf (39.64 MB)

Tipus de document

Article

Versió

Versió publicada

Data de publicació

2024-04-30

Llicència de publicació

cc by-nc-nd (c) Dias, Matheus H. et al.; American Association for Cancer Research, 2024
Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/215109

Paradoxical activation of oncogenic signaling as a cancer treatment strategy

Títol de la revista

Autors

Director/Tutor

ISSN de la revista

Títol del volum

Recurs relacionat

https://doi.org/10.1158/2159-8290.CD-23-0216

Resum

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.

Matèries

Proteïnes quinases, Cicle cel·lular, Càncer colorectal, Resistència als medicaments

Matèries (anglès)

Protein kinases, Cell cycle, Colorectal cancer, Drug resistance

Citació

Col·leccions

Articles publicats en revistes (Ciències Clíniques)
Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))

Citació

DIAS, Matheus h., FRISKES, Anoek, WANG, Siying, FERNANDES NETO, João 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, DA SILVA, Marcelo s., JANSEN, Robin alexandra, MULERO-SÁNCHEZ, Antonio, MALZER, Elke, VIDAL-BEL, August, SANTOS VIVAS, Cristina, SALAZAR SOLER, Ramón, WAILEMANN, Rosangela, PAVAN TORRES, Thompson eusébio, DE CONTI, Giulia, RAAIJMAKERS, Jonne a., SNAEBJORNSSON, Petur, YUAN, Shengxian, QIN, Wenxin, KOVACH, John s., ARMELIN, Hugo a., TE RIELE, Hein, VAN OUDERNAARDEN, Alexander, JIN, Haojie, BEIJERSBERGEN, Roderick l., VILLANUEVA GARATACHEA, Alberto, MEDEMA, René h., BERNARDS, René. Paradoxical activation of oncogenic signaling as a cancer treatment strategy. _Cancer Discovery_. 2024. Vol. 14, núm. 7, pàgs. 1276-1301. [consulta: 24 de gener de 2026]. ISSN: 2159-8274. [Disponible a: https://hdl.handle.net/2445/215109]

Exportar metadades

JSON - METS

Compartir registre