BRAF mutation predicts sensitivity to MEK inhibition (original) (raw)

• Letter
• Published: 06 November 2005
• Levi A. Garraway4,6,
• Christine A. Pratilas2,3,
• Ayana Sawai3,
• Gad Getz6,
• Andrea Basso3 nAff9,
• Qing Ye3,
• Jose M. Lobo3,
• Yuhong She3,
• Iman Osman7,
• Todd R. Golub5,6,
• Judith Sebolt-Leopold8,
• William R. Sellers4,6 &
• …
• Neal Rosen1,3

Nature volume 439, pages 358–362 (2006)Cite this article

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Abstract

The kinase pathway comprising RAS, RAF, mitogen-activated protein kinase kinase (MEK) and extracellular signal regulated kinase (ERK) is activated in most human tumours, often through gain-of-function mutations of RAS and RAF family members1. Using small-molecule inhibitors of MEK and an integrated genetic and pharmacologic analysis, we find that mutation of BRAF is associated with enhanced and selective sensitivity to MEK inhibition when compared to either ‘wild-type’ cells or cells harbouring a RAS mutation. This MEK dependency was observed in BRAF mutant cells regardless of tissue lineage, and correlated with both downregulation of cyclin D1 protein expression and the induction of G1 arrest. Pharmacological MEK inhibition completely abrogated tumour growth in BRAF mutant xenografts, whereas RAS mutant tumours were only partially inhibited. These data suggest an exquisite dependency on MEK activity in BRAF mutant tumours, and offer a rational therapeutic strategy for this genetically defined tumour subtype.

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Acknowledgements

The authors thank H. Ju, W. L. Wong and H. Tseng for technical assistance. This work was supported by grants from the National Institutes of Health (L.A.G., C.A.P., G.G., T.R.G., W.R.S. and N.R.), the William H. Goodwin and Alice Goodwin Foundation for Cancer Research, the MSKCC Experimental Therapeutics Program (D.B.S. and N.R.), the Waxman Foundation (D.B.S. and N.R.), the Howard Hughes Medical Institute (G.G. and T.R.G.), Golfers Against Cancer (D.B.S. and N.R.) and the American Society of Clinical Oncology (D.B.S. and C.A.P.).

Author information

Author notes

1. Andrea Basso
   Present address: Schering-Plough, 2015 Galloping Hill Rd, Kenilworth, New Jersey, 07033, USA

Authors and Affiliations

1. Department of Medicine,
   David B. Solit & Neal Rosen
2. Department of Pediatrics,
   Christine A. Pratilas
3. Department of Molecular Pharmacology and Chemistry, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, 10021, New York, USA
   David B. Solit, Christine A. Pratilas, Ayana Sawai, Andrea Basso, Qing Ye, Jose M. Lobo, Yuhong She & Neal Rosen
4. Department of Medical Oncology,
   Levi A. Garraway & William R. Sellers
5. Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney Street, Massachusetts, 02115, Boston, USA
   Todd R. Golub
6. Broad Institute of Harvard and MIT, 320 Charles Street, Massachusetts, 02141, Cambridge, USA
   Levi A. Garraway, Gad Getz, Todd R. Golub & William R. Sellers
7. Departments of Medicine and Urology, New York University Medical Center, 550 First Avenue, New York, 10016, New York, USA
   Iman Osman
8. Pfizer Global Research and Development, 2800 Plymouth Road, Michigan, 48105, Ann Arbor, USA
   Judith Sebolt-Leopold

Authors

1. David B. Solit
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2. Levi A. Garraway
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3. Christine A. Pratilas
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4. Ayana Sawai
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5. Gad Getz
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6. Andrea Basso
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7. Qing Ye
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8. Jose M. Lobo
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9. Yuhong She
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10. Iman Osman
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11. Todd R. Golub
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12. Judith Sebolt-Leopold
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13. William R. Sellers
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14. Neal Rosen
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Corresponding author

Correspondence toNeal Rosen.

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Competing interests

J.S.-L. is an employee of Pfizer Global Research.

Supplementary information

Supplementary Figure Legends

Legends to accompany the Supplementary Figures and Supplementary Table. (DOC 25 kb)

Supplementary Table 1

Significant Compounds Following Supervised Pharmacologic Analysis of BRAF(V600E) Mutation in NCI60 Cancer Cell Lines. (PDF 55 kb)

Supplementary Figure 1

Hypothemycin causes downregulation of p-ERK and cyclin D1 expression in BRAF(V600E) mutant cells. (PDF 213 kb)

Supplementary Figure 2

PD0325901 selectively inhibits the growth of BRAF mutant cell lines. (PDF 61 kb)

Supplementary Figure 3

Sensitivity of Colo205 and SKMEL30 xenograft tumours to the MEK inhibitor PD0325901. (PDF 16 kb)

Supplementary Figure 4

dSensitivity of xenograft tumours to PD0325901 does not correlate with basal levels of p-ERK. (PDF 137 kb)

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Solit, D., Garraway, L., Pratilas, C. et al. BRAF mutation predicts sensitivity to MEK inhibition.Nature 439, 358–362 (2006). https://doi.org/10.1038/nature04304

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• Received: 10 May 2005
• Accepted: 04 October 2005
• Published: 06 November 2005
• Issue Date: 19 January 2006
• DOI: https://doi.org/10.1038/nature04304

Editorial Summary

Tumour profiling advances

Molecular tumour profiling is one way in which effective targeted cancer treatment regimes might be developed. Two groups report significant developments in this direction. Bild et al. studied gene expression patterns that reflect the activation of various oncogenic (cancer-causing) signal transduction pathways. Using combinations of these pathway signatures, they predict which patients with breast, lung or ovarian cancer have a particularly poor prognosis. The ability to identify molecular pathways that are deregulated in a particular cancer in this way might be used to predict its sensitivity to specific therapeutic drugs. Solit et al. studied tumour cells with mutations in the RAS and BRAF genes, thought to cause cancer at least in part by activating the MEK/ERK signalling pathway. They show that tumours with the BRAF mutation, but not RAS, are highly sensitive to PD0325901, an MEK inhibitor that is in early-stage clinical trials in patients with melanoma, colon, breast and lung cancers. So by testing for the presence of BRAF mutations it may be possible to identify those patients most likely to benefit from this type of drug.

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