Paradoxical Activation of Oncogenic Signaling as a Cancer Treatment Strategy

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

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

Paradoxical Activation of Oncogenic Signaling as a Cancer Treatment Strategy

Matheus Henrique Dias, Anoek Friskes, Siying Wang, Joao M Fernandes Neto, Frank van Gemert, Soufiane Mourragui, Chrysa Papagianni, Hendrik J Kuiken, Sara Mainardi, Daniel Alvarez-Villanueva, Cor Lieftink, Ben Morris, Anna Dekker, Emma van Dijk, Lieke H S Wilms, Marcelo S da Silva, Robin A Jansen, Antonio Mulero-Sánchez, Elke Malzer, August VidalCristina Santos, Ramón Salazar, Rosangela A M Wailemann, Thompson E P Torres, Giulia De Conti, Jonne A Raaijmakers, Petur Snaebjornsson, Shengxian Yuan, Wenxin Qin, John S Kovach, Hugo A Armelin, Hein Te Riele, Alexander van Oudenaarden, Haojie Jin, Roderick L Beijersbergen, Alberto Villanueva, Rene H Medema, Rene Bernards

Hubrecht Institute

Research output: Contribution to journal/periodical › Article › Scientific › peer-review

10 Citations (Scopus)

Abstract

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.

Original language	English
Pages (from-to)	1276-1301
Number of pages	26
Journal	Cancer Discovery
Volume	14
Issue number	7
DOIs	https://doi.org/10.1158/2159-8290.CD-23-0216
Publication status	Published - 01 Jul 2024

Keywords

Humans
Signal Transduction
Animals
Protein Phosphatase 2/metabolism
Mice
Cell Line, Tumor
Colonic Neoplasms/drug therapy
Xenograft Model Antitumor Assays
Cell Cycle Proteins/metabolism
Protein-Tyrosine Kinases/antagonists & inhibitors
Drug Resistance, Neoplasm
Nuclear Proteins/metabolism
DNA Replication

Access to Document

10.1158/2159-8290.CD-23-0216

Cite this

Dias, M. H., Friskes, A., Wang, S., Fernandes Neto, J. M., van Gemert, F., Mourragui, S., Papagianni, C., Kuiken, H. J., Mainardi, S., Alvarez-Villanueva, D., Lieftink, C., Morris, B., Dekker, A., van Dijk, E., Wilms, L. H. S., da Silva, M. S., Jansen, R. A., Mulero-Sánchez, A., Malzer, E., ... Bernards, R. (2024). Paradoxical Activation of Oncogenic Signaling as a Cancer Treatment Strategy. Cancer Discovery, 14(7), 1276-1301. https://doi.org/10.1158/2159-8290.CD-23-0216

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title = "Paradoxical Activation of Oncogenic Signaling as a Cancer Treatment Strategy",

abstract = "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.",

keywords = "Humans, Signal Transduction, Animals, Protein Phosphatase 2/metabolism, Mice, Cell Line, Tumor, Colonic Neoplasms/drug therapy, Xenograft Model Antitumor Assays, Cell Cycle Proteins/metabolism, Protein-Tyrosine Kinases/antagonists & inhibitors, Drug Resistance, Neoplasm, Nuclear Proteins/metabolism, DNA Replication",

author = "Dias, {Matheus Henrique} and Anoek Friskes and Siying Wang and {Fernandes Neto}, {Joao M} and {van Gemert}, Frank and Soufiane Mourragui and Chrysa Papagianni and Kuiken, {Hendrik J} and Sara Mainardi and Daniel Alvarez-Villanueva and Cor Lieftink and Ben Morris and Anna Dekker and {van Dijk}, Emma and Wilms, {Lieke H S} and {da Silva}, {Marcelo S} and Jansen, {Robin A} and Antonio Mulero-S{\'a}nchez and Elke Malzer and August Vidal and Cristina Santos and Ram{\'o}n Salazar and Wailemann, {Rosangela A M} and Torres, {Thompson E P} and {De Conti}, Giulia and Raaijmakers, {Jonne A} and Petur Snaebjornsson and Shengxian Yuan and Wenxin Qin and Kovach, {John S} and Armelin, {Hugo A} and {Te Riele}, Hein and {van Oudenaarden}, Alexander and Haojie Jin and Beijersbergen, {Roderick L} and Alberto Villanueva and Medema, {Rene H} and Rene Bernards",

note = "{\textcopyright}2024 The Authors; Published by the American Association for Cancer Research.",

year = "2024",

month = jul,

day = "1",

doi = "10.1158/2159-8290.CD-23-0216",

language = "English",

volume = "14",

pages = "1276--1301",

journal = "Cancer Discovery",

issn = "2159-8274",

publisher = "American Association for Cancer Research Inc.",

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Dias, MH, Friskes, A, Wang, S, Fernandes Neto, JM, van Gemert, F, Mourragui, S, Papagianni, C, Kuiken, HJ, Mainardi, S, Alvarez-Villanueva, D, Lieftink, C, Morris, B, Dekker, A, van Dijk, E, Wilms, LHS, da Silva, MS, Jansen, RA, Mulero-Sánchez, A, Malzer, E, Vidal, A, Santos, C, Salazar, R, Wailemann, RAM, Torres, TEP, De Conti, G, Raaijmakers, JA, Snaebjornsson, P, Yuan, S, Qin, W, Kovach, JS, Armelin, HA, Te Riele, H, van Oudenaarden, A, Jin, H, Beijersbergen, RL, Villanueva, A, Medema, RH & Bernards, R 2024, 'Paradoxical Activation of Oncogenic Signaling as a Cancer Treatment Strategy', Cancer Discovery, vol. 14, no. 7, pp. 1276-1301. https://doi.org/10.1158/2159-8290.CD-23-0216

TY - JOUR

T1 - Paradoxical Activation of Oncogenic Signaling as a Cancer Treatment Strategy

AU - Dias, Matheus Henrique

AU - Friskes, Anoek

AU - Wang, Siying

AU - Fernandes Neto, Joao M

AU - van Gemert, Frank

AU - Mourragui, Soufiane

AU - Papagianni, Chrysa

AU - Kuiken, Hendrik J

AU - Mainardi, Sara

AU - Alvarez-Villanueva, Daniel

AU - Lieftink, Cor

AU - Morris, Ben

AU - Dekker, Anna

AU - van Dijk, Emma

AU - Wilms, Lieke H S

AU - da Silva, Marcelo S

AU - Jansen, Robin A

AU - Mulero-Sánchez, Antonio

AU - Malzer, Elke

AU - Vidal, August

AU - Santos, Cristina

AU - Salazar, Ramón

AU - Wailemann, Rosangela A M

AU - Torres, Thompson E P

AU - De Conti, Giulia

AU - Raaijmakers, Jonne A

AU - Snaebjornsson, Petur

AU - Yuan, Shengxian

AU - Qin, Wenxin

AU - Kovach, John S

AU - Armelin, Hugo A

AU - Te Riele, Hein

AU - van Oudenaarden, Alexander

AU - Jin, Haojie

AU - Beijersbergen, Roderick L

AU - Villanueva, Alberto

AU - Medema, Rene H

AU - Bernards, Rene

PY - 2024/7/1

Y1 - 2024/7/1

N2 - 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.

AB - 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.

KW - Humans

KW - Signal Transduction

KW - Animals

KW - Protein Phosphatase 2/metabolism

KW - Mice

KW - Cell Line, Tumor

KW - Colonic Neoplasms/drug therapy

KW - Xenograft Model Antitumor Assays

KW - Cell Cycle Proteins/metabolism

KW - Protein-Tyrosine Kinases/antagonists & inhibitors

KW - Drug Resistance, Neoplasm

KW - Nuclear Proteins/metabolism

KW - DNA Replication

U2 - 10.1158/2159-8290.CD-23-0216

DO - 10.1158/2159-8290.CD-23-0216

M3 - Article

C2 - 38533987

SN - 2159-8274

VL - 14

SP - 1276

EP - 1301

JO - Cancer Discovery

JF - Cancer Discovery

IS - 7

ER -