Paradoxical Activation of Oncogenic Signaling as a Cancer Treatment Strategy.

Autor:	Dias MH; Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, the Netherlands., Friskes A; Division of Cell Biology, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, the Netherlands., Wang S; State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China., Fernandes Neto JM; Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, the Netherlands., van Gemert F; Division of Tumor Biology and Immunology, The Netherlands Cancer Institute, Amsterdam, the Netherlands., Mourragui S; Hubrecht Institute-KNAW (Royal Netherlands Academy of Arts and Sciences) and University Medical Center, Utrecht, the Netherlands., Papagianni C; Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, the Netherlands., Kuiken HJ; Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam, the Netherlands., Mainardi S; Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, the Netherlands., Alvarez-Villanueva D; Chemoresistance and Predictive Factors Group, Program Against Cancer Therapeutic Resistance (ProCURE), Catalan Institute of Oncology (ICO), Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet del Llobregat, Barcelona, Spain., Lieftink C; Division of Molecular Carcinogenesis, NKI Robotic and Screening Center, The Netherlands Cancer Institute, Amsterdam, the Netherlands., Morris B; Division of Molecular Carcinogenesis, NKI Robotic and Screening Center, The Netherlands Cancer Institute, Amsterdam, the Netherlands., Dekker A; Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, the Netherlands., van Dijk E; Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, the Netherlands., Wilms LHS; Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, the Netherlands., da Silva MS; Department of Biochemistry, Institute of Chemistry, University of São Paulo, São Paulo, SP, Brazil.; Department of Chemical and Biological Sciences, Institute of Biosciences, São Paulo State University (UNESP), Botucatu, SP, Brazil., Jansen RA; Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, the Netherlands., Mulero-Sánchez A; Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, the Netherlands., Malzer E; Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam, the Netherlands., Vidal A; Department of Pathology, University Hospital of Bellvitge, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.; Xenopat S.L., Parc Cientific de Barcelona (PCB), Barcelona, Spain., Santos C; Department of Medical Oncology, Catalan Institute of Oncology (ICO), Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), CIBERONC, Barcelona, Spain., Salazar R; Department of Medical Oncology, Catalan Institute of Oncology (ICO), Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), CIBERONC, Barcelona, Spain., Wailemann RAM; Center of Toxins, Immune-response and Cell Signaling, Instituto Butantan, São Paulo, Brazil., Torres TEP; Center of Toxins, Immune-response and Cell Signaling, Instituto Butantan, São Paulo, Brazil.; Department of Clinical and Experimental Oncology, Federal University of São Paulo (UNIFESP), São Paulo, Brazil., De Conti G; Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, the Netherlands., Raaijmakers JA; Division of Cell Biology, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, the Netherlands., Snaebjornsson P; Department of Pathology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.; University of Iceland, Faculty of Medicine, Reykjavik, Iceland., Yuan S; The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Shanghai, China., Qin W; State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China., Kovach JS; Lixte Biotechnology Holdings, Inc., Pasadena, California., Armelin HA; Center of Toxins, Immune-response and Cell Signaling, Instituto Butantan, São Paulo, Brazil., Te Riele H; Division of Tumor Biology and Immunology, The Netherlands Cancer Institute, Amsterdam, the Netherlands., van Oudenaarden A; Hubrecht Institute-KNAW (Royal Netherlands Academy of Arts and Sciences) and University Medical Center, Utrecht, the Netherlands., Jin H; Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, the Netherlands.; State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China., Beijersbergen RL; Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam, the Netherlands.; Division of Molecular Carcinogenesis, NKI Robotic and Screening Center, The Netherlands Cancer Institute, Amsterdam, the Netherlands., Villanueva A; Chemoresistance and Predictive Factors Group, Program Against Cancer Therapeutic Resistance (ProCURE), Catalan Institute of Oncology (ICO), Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet del Llobregat, Barcelona, Spain.; Xenopat S.L., Parc Cientific de Barcelona (PCB), Barcelona, Spain., Medema RH; Division of Cell Biology, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, the Netherlands., Bernards R; Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
Jazyk:	angličtina
Zdroj:	Cancer discovery [Cancer Discov] 2024 Jul 01; Vol. 14 (7), pp. 1276-1301.
DOI:	10.1158/2159-8290.CD-23-0216
Abstrakt:	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. (©2024 The Authors; Published by the American Association for Cancer Research.)
Databáze:	MEDLINE
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