KRAS Dimerization Impacts MEK Inhibitor Sensitivity and Oncogenic Activity of Mutant KRAS

Chiara Ambrogio; Jens Köhler; Zhi Wei Zhou; Haiyun Wang; Raymond Paranal; Jiaqi Li; Marzia Capelletti; Cristina Caffarra; Shuai Li; Qi Lv; Sudershan Gondi; John C. Hunter; Jia Lu; Roberto Chiarle; David Santamaría; Kenneth D. Westover; Pasi A. Jänne

doi:10.1016/j.cell.2017.12.020

KRAS Dimerization Impacts MEK Inhibitor Sensitivity and Oncogenic Activity of Mutant KRAS

Chiara Ambrogio, Jens Köhler, Zhi Wei Zhou, Haiyun Wang, Raymond Paranal, Jiaqi Li, Marzia Capelletti, Cristina Caffarra, Shuai Li, Qi Lv, Sudershan Gondi, John C. Hunter, Jia Lu, Roberto Chiarle, David Santamaría, Kenneth D. Westover, Pasi A. Jänne

Research output: Contribution to journal › Article › peer-review

191 Scopus citations

Abstract

The mechanism by which the wild-type KRAS allele imparts a growth inhibitory effect to oncogenic KRAS in various cancers, including lung adenocarcinoma (LUAD), is poorly understood. Here, using a genetically inducible model of KRAS loss of heterozygosity (LOH), we show that KRAS dimerization mediates wild-type KRAS-dependent fitness of human and murine KRAS mutant LUAD tumor cells and underlies resistance to MEK inhibition. These effects are abrogated when wild-type KRAS is replaced by KRAS^D154Q, a mutant that disrupts dimerization at the α4-α5 KRAS dimer interface without changing other fundamental biochemical properties of KRAS, both in vitro and in vivo. Moreover, dimerization has a critical role in the oncogenic activity of mutant KRAS. Our studies provide mechanistic and biological insights into the role of KRAS dimerization and highlight a role for disruption of dimerization as a therapeutic strategy for KRAS mutant cancers. The tumor-suppressive function of wild-type KRAS depends on its dimerization capacity with mutant KRAS.

Original language	English (US)
Pages (from-to)	857-868.e15
Journal	Cell
Volume	172
Issue number	4
DOIs	https://doi.org/10.1016/j.cell.2017.12.020
State	Published - Feb 8 2018

Keywords

KRAS oncogene
MAPK pathway
MEK inhibitors
allelic imbalance
dimerization
drug resistance
lung adenocarcinoma
wild-type allele

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.cell.2017.12.020

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Ambrogio, C., Köhler, J., Zhou, Z. W., Wang, H., Paranal, R., Li, J., Capelletti, M., Caffarra, C., Li, S., Lv, Q., Gondi, S., Hunter, J. C., Lu, J., Chiarle, R., Santamaría, D., Westover, K. D., & Jänne, P. A. (2018). KRAS Dimerization Impacts MEK Inhibitor Sensitivity and Oncogenic Activity of Mutant KRAS. Cell, 172(4), 857-868.e15. https://doi.org/10.1016/j.cell.2017.12.020

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title = "KRAS Dimerization Impacts MEK Inhibitor Sensitivity and Oncogenic Activity of Mutant KRAS",

abstract = "The mechanism by which the wild-type KRAS allele imparts a growth inhibitory effect to oncogenic KRAS in various cancers, including lung adenocarcinoma (LUAD), is poorly understood. Here, using a genetically inducible model of KRAS loss of heterozygosity (LOH), we show that KRAS dimerization mediates wild-type KRAS-dependent fitness of human and murine KRAS mutant LUAD tumor cells and underlies resistance to MEK inhibition. These effects are abrogated when wild-type KRAS is replaced by KRASD154Q, a mutant that disrupts dimerization at the α4-α5 KRAS dimer interface without changing other fundamental biochemical properties of KRAS, both in vitro and in vivo. Moreover, dimerization has a critical role in the oncogenic activity of mutant KRAS. Our studies provide mechanistic and biological insights into the role of KRAS dimerization and highlight a role for disruption of dimerization as a therapeutic strategy for KRAS mutant cancers. The tumor-suppressive function of wild-type KRAS depends on its dimerization capacity with mutant KRAS.",

keywords = "KRAS oncogene, MAPK pathway, MEK inhibitors, allelic imbalance, dimerization, drug resistance, lung adenocarcinoma, wild-type allele",

author = "Chiara Ambrogio and Jens K{\"o}hler and Zhou, {Zhi Wei} and Haiyun Wang and Raymond Paranal and Jiaqi Li and Marzia Capelletti and Cristina Caffarra and Shuai Li and Qi Lv and Sudershan Gondi and Hunter, {John C.} and Jia Lu and Roberto Chiarle and David Santamar{\'i}a and Westover, {Kenneth D.} and J{\"a}nne, {Pasi A.}",

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year = "2018",

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doi = "10.1016/j.cell.2017.12.020",

language = "English (US)",

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T1 - KRAS Dimerization Impacts MEK Inhibitor Sensitivity and Oncogenic Activity of Mutant KRAS

AU - Ambrogio, Chiara

AU - Köhler, Jens

AU - Zhou, Zhi Wei

AU - Wang, Haiyun

AU - Paranal, Raymond

AU - Li, Jiaqi

AU - Capelletti, Marzia

AU - Caffarra, Cristina

AU - Li, Shuai

AU - Lv, Qi

AU - Gondi, Sudershan

AU - Hunter, John C.

AU - Lu, Jia

AU - Chiarle, Roberto

AU - Santamaría, David

AU - Westover, Kenneth D.

AU - Jänne, Pasi A.

PY - 2018/2/8

Y1 - 2018/2/8

N2 - The mechanism by which the wild-type KRAS allele imparts a growth inhibitory effect to oncogenic KRAS in various cancers, including lung adenocarcinoma (LUAD), is poorly understood. Here, using a genetically inducible model of KRAS loss of heterozygosity (LOH), we show that KRAS dimerization mediates wild-type KRAS-dependent fitness of human and murine KRAS mutant LUAD tumor cells and underlies resistance to MEK inhibition. These effects are abrogated when wild-type KRAS is replaced by KRASD154Q, a mutant that disrupts dimerization at the α4-α5 KRAS dimer interface without changing other fundamental biochemical properties of KRAS, both in vitro and in vivo. Moreover, dimerization has a critical role in the oncogenic activity of mutant KRAS. Our studies provide mechanistic and biological insights into the role of KRAS dimerization and highlight a role for disruption of dimerization as a therapeutic strategy for KRAS mutant cancers. The tumor-suppressive function of wild-type KRAS depends on its dimerization capacity with mutant KRAS.

AB - The mechanism by which the wild-type KRAS allele imparts a growth inhibitory effect to oncogenic KRAS in various cancers, including lung adenocarcinoma (LUAD), is poorly understood. Here, using a genetically inducible model of KRAS loss of heterozygosity (LOH), we show that KRAS dimerization mediates wild-type KRAS-dependent fitness of human and murine KRAS mutant LUAD tumor cells and underlies resistance to MEK inhibition. These effects are abrogated when wild-type KRAS is replaced by KRASD154Q, a mutant that disrupts dimerization at the α4-α5 KRAS dimer interface without changing other fundamental biochemical properties of KRAS, both in vitro and in vivo. Moreover, dimerization has a critical role in the oncogenic activity of mutant KRAS. Our studies provide mechanistic and biological insights into the role of KRAS dimerization and highlight a role for disruption of dimerization as a therapeutic strategy for KRAS mutant cancers. The tumor-suppressive function of wild-type KRAS depends on its dimerization capacity with mutant KRAS.

KW - KRAS oncogene

KW - MAPK pathway

KW - MEK inhibitors

KW - allelic imbalance

KW - dimerization

KW - drug resistance

KW - lung adenocarcinoma

KW - wild-type allele

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VL - 172

SP - 857-868.e15

JO - Cell

JF - Cell

IS - 4

ER -

KRAS Dimerization Impacts MEK Inhibitor Sensitivity and Oncogenic Activity of Mutant KRAS

Abstract

Keywords

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