MAP3K1 and MAP2K4 mutations are associated with sensitivity to MEK inhibitors in multiple cancer models

Zheng Xue; Daniel J Vis; Alejandra Bruna; Tonci Sustic; Sake van Wageningen; Ankita Sati Batra; Oscar M Rueda; Evert Bosdriesz; Carlos Caldas; Lodewyk F A Wessels; René Bernards

doi:10.1038/s41422-018-0044-4

MAP3K1 and MAP2K4 mutations are associated with sensitivity to MEK inhibitors in multiple cancer models

Zheng Xue, Daniel J Vis, Alejandra Bruna, Tonci Sustic, Sake van Wageningen, Ankita Sati Batra, Oscar M Rueda, Evert Bosdriesz, Carlos Caldas, Lodewyk F A Wessels, René Bernards

Bioinformatics

Research output: Contribution to Journal › Article › Academic › peer-review

Abstract

Activation of the mitogen-activated protein kinase (MAPK) pathway is frequent in cancer. Drug development efforts have been focused on kinases in this pathway, most notably on RAF and MEK. We show here that MEK inhibition activates JNK-JUN signaling through suppression of DUSP4, leading to activation of HER Receptor Tyrosine Kinases. This stimulates the MAPK pathway in the presence of drug, thereby blunting the effect of MEK inhibition. Cancers that have lost MAP3K1 or MAP2K4 fail to activate JNK-JUN. Consequently, loss-of-function mutations in either MAP3K1 or MAP2K4 confer sensitivity to MEK inhibition by disabling JNK-JUN-mediated feedback loop upon MEK inhibition. In a panel of 168 Patient Derived Xenograft (PDX) tumors, MAP3K1 and MAP2K4 mutation status is a strong predictor of response to MEK inhibition. Our findings suggest that cancers having mutations in MAP3K1 or MAP2K4, which are frequent in tumors of breast, prostate and colon, may respond to MEK inhibitors. Our findings also suggest that MAP3K1 and MAP2K4 are potential drug targets in combination with MEK inhibitors, in spite of the fact that they are encoded by tumor suppressor genes.

Original language	English
Pages (from-to)	719-729
Number of pages	11
Journal	Cell Research
Volume	28
Issue number	7
DOIs	https://doi.org/10.1038/s41422-018-0044-4
Publication status	Published - Jul 2018

Funding

We thank Ian Majewski for kind assistance with some of the experiments. We also acknowledge Astrid Bosma for help with DNA sequence analyses and Magali Michaut for bioinformatics support. We would like to thank the people from the Preclinical Intervention Unit of the Mouse Clinic for Cancer and Ageing (MCCA) at the NKI for performing the intervention studies. This work was supported by EU FP7 grant “RATHER” and by the Dutch Cancer Society and by financial support from Astex (Cambridge, UK). This work was funded in part through a research grant from Astex pharmaceuticals.

Funders	Funder number
Dutch Cancer Society
EU FP7

Keywords

Animals
Benzimidazoles/pharmacology
Breast Neoplasms/drug therapy
Cell Line, Tumor
Colonic Neoplasms/drug therapy
Drug Resistance, Neoplasm/genetics
Female
Heterografts
Humans
Loss of Function Mutation
MAP Kinase Kinase 4/antagonists & inhibitors
MAP Kinase Kinase Kinase 1/antagonists & inhibitors
MAP Kinase Signaling System/drug effects
Male
Mice, Inbred BALB C
Mice, Nude
Mitogen-Activated Protein Kinase Kinases/antagonists & inhibitors
Prostatic Neoplasms/drug therapy
Protein Kinase Inhibitors/pharmacology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41422-018-0044-4

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title = "MAP3K1 and MAP2K4 mutations are associated with sensitivity to MEK inhibitors in multiple cancer models",

abstract = "Activation of the mitogen-activated protein kinase (MAPK) pathway is frequent in cancer. Drug development efforts have been focused on kinases in this pathway, most notably on RAF and MEK. We show here that MEK inhibition activates JNK-JUN signaling through suppression of DUSP4, leading to activation of HER Receptor Tyrosine Kinases. This stimulates the MAPK pathway in the presence of drug, thereby blunting the effect of MEK inhibition. Cancers that have lost MAP3K1 or MAP2K4 fail to activate JNK-JUN. Consequently, loss-of-function mutations in either MAP3K1 or MAP2K4 confer sensitivity to MEK inhibition by disabling JNK-JUN-mediated feedback loop upon MEK inhibition. In a panel of 168 Patient Derived Xenograft (PDX) tumors, MAP3K1 and MAP2K4 mutation status is a strong predictor of response to MEK inhibition. Our findings suggest that cancers having mutations in MAP3K1 or MAP2K4, which are frequent in tumors of breast, prostate and colon, may respond to MEK inhibitors. Our findings also suggest that MAP3K1 and MAP2K4 are potential drug targets in combination with MEK inhibitors, in spite of the fact that they are encoded by tumor suppressor genes.",

keywords = "Animals, Benzimidazoles/pharmacology, Breast Neoplasms/drug therapy, Cell Line, Tumor, Colonic Neoplasms/drug therapy, Drug Resistance, Neoplasm/genetics, Female, Heterografts, Humans, Loss of Function Mutation, MAP Kinase Kinase 4/antagonists \& inhibitors, MAP Kinase Kinase Kinase 1/antagonists \& inhibitors, MAP Kinase Signaling System/drug effects, Male, Mice, Inbred BALB C, Mice, Nude, Mitogen-Activated Protein Kinase Kinases/antagonists \& inhibitors, Prostatic Neoplasms/drug therapy, Protein Kinase Inhibitors/pharmacology",

author = "Zheng Xue and Vis, \{Daniel J\} and Alejandra Bruna and Tonci Sustic and \{van Wageningen\}, Sake and Batra, \{Ankita Sati\} and Rueda, \{Oscar M\} and Evert Bosdriesz and Carlos Caldas and Wessels, \{Lodewyk F A\} and Ren{\'e} Bernards",

year = "2018",

month = jul,

doi = "10.1038/s41422-018-0044-4",

language = "English",

volume = "28",

pages = "719--729",

journal = "Cell Research",

issn = "1001-0602",

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TY - JOUR

T1 - MAP3K1 and MAP2K4 mutations are associated with sensitivity to MEK inhibitors in multiple cancer models

AU - Xue, Zheng

AU - Vis, Daniel J

AU - Bruna, Alejandra

AU - Sustic, Tonci

AU - van Wageningen, Sake

AU - Batra, Ankita Sati

AU - Rueda, Oscar M

AU - Bosdriesz, Evert

AU - Caldas, Carlos

AU - Wessels, Lodewyk F A

AU - Bernards, René

PY - 2018/7

Y1 - 2018/7

N2 - Activation of the mitogen-activated protein kinase (MAPK) pathway is frequent in cancer. Drug development efforts have been focused on kinases in this pathway, most notably on RAF and MEK. We show here that MEK inhibition activates JNK-JUN signaling through suppression of DUSP4, leading to activation of HER Receptor Tyrosine Kinases. This stimulates the MAPK pathway in the presence of drug, thereby blunting the effect of MEK inhibition. Cancers that have lost MAP3K1 or MAP2K4 fail to activate JNK-JUN. Consequently, loss-of-function mutations in either MAP3K1 or MAP2K4 confer sensitivity to MEK inhibition by disabling JNK-JUN-mediated feedback loop upon MEK inhibition. In a panel of 168 Patient Derived Xenograft (PDX) tumors, MAP3K1 and MAP2K4 mutation status is a strong predictor of response to MEK inhibition. Our findings suggest that cancers having mutations in MAP3K1 or MAP2K4, which are frequent in tumors of breast, prostate and colon, may respond to MEK inhibitors. Our findings also suggest that MAP3K1 and MAP2K4 are potential drug targets in combination with MEK inhibitors, in spite of the fact that they are encoded by tumor suppressor genes.

AB - Activation of the mitogen-activated protein kinase (MAPK) pathway is frequent in cancer. Drug development efforts have been focused on kinases in this pathway, most notably on RAF and MEK. We show here that MEK inhibition activates JNK-JUN signaling through suppression of DUSP4, leading to activation of HER Receptor Tyrosine Kinases. This stimulates the MAPK pathway in the presence of drug, thereby blunting the effect of MEK inhibition. Cancers that have lost MAP3K1 or MAP2K4 fail to activate JNK-JUN. Consequently, loss-of-function mutations in either MAP3K1 or MAP2K4 confer sensitivity to MEK inhibition by disabling JNK-JUN-mediated feedback loop upon MEK inhibition. In a panel of 168 Patient Derived Xenograft (PDX) tumors, MAP3K1 and MAP2K4 mutation status is a strong predictor of response to MEK inhibition. Our findings suggest that cancers having mutations in MAP3K1 or MAP2K4, which are frequent in tumors of breast, prostate and colon, may respond to MEK inhibitors. Our findings also suggest that MAP3K1 and MAP2K4 are potential drug targets in combination with MEK inhibitors, in spite of the fact that they are encoded by tumor suppressor genes.

KW - Animals

KW - Benzimidazoles/pharmacology

KW - Breast Neoplasms/drug therapy

KW - Cell Line, Tumor

KW - Colonic Neoplasms/drug therapy

KW - Drug Resistance, Neoplasm/genetics

KW - Female

KW - Heterografts

KW - Humans

KW - Loss of Function Mutation

KW - MAP Kinase Kinase 4/antagonists & inhibitors

KW - MAP Kinase Kinase Kinase 1/antagonists & inhibitors

KW - MAP Kinase Signaling System/drug effects

KW - Male

KW - Mice, Inbred BALB C

KW - Mice, Nude

KW - Mitogen-Activated Protein Kinase Kinases/antagonists & inhibitors

KW - Prostatic Neoplasms/drug therapy

KW - Protein Kinase Inhibitors/pharmacology

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U2 - 10.1038/s41422-018-0044-4

DO - 10.1038/s41422-018-0044-4

M3 - Article

C2 - 29795445

SN - 1001-0602

VL - 28

SP - 719

EP - 729

JO - Cell Research

JF - Cell Research

IS - 7

ER -

MAP3K1 and MAP2K4 mutations are associated with sensitivity to MEK inhibitors in multiple cancer models

Abstract

Funding

Keywords

UN SDGs

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