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 journalArticle

49 Citations (Scopus)

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.

Original languageEnglish (US)
JournalCell
DOIs
StateAccepted/In press - Jan 1 2018

Fingerprint

Dimerization
Mitogen-Activated Protein Kinase Kinases
Tumors
Neoplasms
Loss of Heterozygosity
Dimers
Lung Neoplasms
Alleles
Cells
Growth

Keywords

  • Allelic imbalance
  • Dimerization
  • Drug resistance
  • KRAS oncogene
  • Lung adenocarcinoma
  • MAPK pathway
  • MEK inhibitors
  • Wild-type allele

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Ambrogio, C., Köhler, J., Zhou, Z. W., Wang, H., Paranal, R., Li, J., ... Jänne, P. A. (Accepted/In press). KRAS Dimerization Impacts MEK Inhibitor Sensitivity and Oncogenic Activity of Mutant KRAS. Cell. https://doi.org/10.1016/j.cell.2017.12.020

KRAS Dimerization Impacts MEK Inhibitor Sensitivity and Oncogenic Activity of Mutant KRAS. / Ambrogio, Chiara; Köhler, Jens; Zhou, Zhi Wei; Wang, Haiyun; Paranal, Raymond; Li, Jiaqi; Capelletti, Marzia; Caffarra, Cristina; Li, Shuai; Lv, Qi; Gondi, Sudershan; Hunter, John C.; Lu, Jia; Chiarle, Roberto; Santamaría, David; Westover, Kenneth D.; Jänne, Pasi A.

In: Cell, 01.01.2018.

Research output: Contribution to journalArticle

Ambrogio, C, Köhler, J, Zhou, ZW, Wang, H, Paranal, R, Li, J, Capelletti, M, Caffarra, C, Li, S, Lv, Q, Gondi, S, Hunter, JC, Lu, J, Chiarle, R, Santamaría, D, Westover, KD & Jänne, PA 2018, 'KRAS Dimerization Impacts MEK Inhibitor Sensitivity and Oncogenic Activity of Mutant KRAS', Cell. https://doi.org/10.1016/j.cell.2017.12.020
Ambrogio, Chiara ; Köhler, Jens ; Zhou, Zhi Wei ; Wang, Haiyun ; Paranal, Raymond ; Li, Jiaqi ; Capelletti, Marzia ; Caffarra, Cristina ; Li, Shuai ; Lv, Qi ; Gondi, Sudershan ; Hunter, John C. ; Lu, Jia ; Chiarle, Roberto ; Santamaría, David ; Westover, Kenneth D. ; Jänne, Pasi A. / KRAS Dimerization Impacts MEK Inhibitor Sensitivity and Oncogenic Activity of Mutant KRAS. In: Cell. 2018.
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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.",
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AU - Ambrogio, Chiara

AU - Köhler, Jens

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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 - 2018/1/1

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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.

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KW - KRAS oncogene

KW - Lung adenocarcinoma

KW - MAPK pathway

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KW - Wild-type allele

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