Paper

Paradoxical activation of oncogenic signaling as a cancer treatment strategy

Malzer, Elke, Morris, Ben, Vidal, August, Raaijmakers, Jonne, Snaebjornsson, Petur, Mainardi, Sara, Papagianni, Chrysa, Qin, Wenxin, Frank Van Gemert, Wailemann, Rosangela A M, Alexander Van Oudenaarden, Emma Van Dijk, Hein Te Riele, Medema, Rene H, Santos, Cristina, Yuan, Shengxian, Lieftink, Cor, Marcelo Santos Da Silva, Dias, Matheus Henrique, Alvarez-Villanueva, Daniel, Joao Manuel Henrique Fernandes Neto, De Conti, Giulia, Jansen, Robin, Beijersbergen, Roderick, Dekker, Anna, Wang, Siying, Hugo Aguirre Armelin, Kovach, John S, Mulero-Sanchez, Antonio, Kuiken, Hendrik Johan, Bernards, Rene, Friskes, Anoek, Jin, Haojie, Salazar, Ramon, Mourragui, Soufiane, Villanueva, Alberto, Thompson Ep Torres

2023

Overview

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. While 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.Competing Interest StatementR.B., J.K. and M.H.D are listed as inventors of a patent describing the drug combinations discovered here. R.B. is a member of the board of directors of Lixte Biotechnology. R.B and M.H.D. are shareholders of Lixte Biotechnology. J.K. is employee of Lixte and shareholder in the company. This work was supported in part by a research grant for Lixte Biotechnology. A.V. and A.Vil. are co-founders of Xenopat S.L.

• Publisher: Cold Spring Harbor Laboratory Press,Cold Spring Harbor Laboratory
• Subject: Biotechnology / Cancer Biology / Cancer therapies / Cell death / Cellular stress response / Colon cancer / Colorectal cancer / DNA biosynthesis / Homeostasis / Lethality / Mitosis / Phosphoprotein phosphatase / Protein phosphatase / Signal transduction / Toxicity / Tumorigenesis / Tumors