The RAC1 P29S hotspot mutation in melanoma confers resistance to pharmacological inhibition of RAF

Ian R. Watson, Liren Li, Peter K. Cabeceiras, Mozhdeh Mahdavi, Tony Gutschner, Giannicola Genovese, Guocan Wang, Zhuangna Fang, James M. Tepper, Katherine Stemke-Hale, Kenneth Y. Tsai, Michael A. Davies, Gordon Mills, Lynda Chin

Research output: Contribution to journalArticle

55 Citations (Scopus)

Abstract

Following mutations in BRAF and NRAS, the RAC1 c.85C>T single-nucleotide variant (SNV) encoding P29S amino acid change represents the next most frequently observed protein-coding hotspot mutation in melanoma. However, the biologic and clinical significance of the RAC1 P29S somatic mutation in approximately 4% to 9% of patients remains unclear. Here, we demonstrate that melanoma cell lines possessing the RAC1 hotspot variant are resistant to RAF inhibitors (vemurafenib and dabrafenib). Enforced expression of RAC1 P29S in sensitive BRAFmutant melanoma cell lines confers resistance manifested by increased viability, decreased apoptosis, and enhanced tumor growth in vivo upon treatment with RAF inhibitors. Conversely, RNAi-mediated silencing of endogenous RAC1 P29S in a melanoma cell line with a co-occurring BRAF V600 mutation increased sensitivity to vemurafenib and dabrafenib. Our results suggest RAC1 P29S status may offer a predictive biomarker for RAF inhibitor resistance in melanoma patients, where it should be evaluated clinically.

Original languageEnglish (US)
Pages (from-to)4845-4852
Number of pages8
JournalCancer Research
Volume74
Issue number17
DOIs
StatePublished - Sep 1 2014
Externally publishedYes

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Melanoma
Pharmacology
Mutation
Cell Line
RNA Interference
Nucleotides
Biomarkers
Apoptosis
Amino Acids
Growth
Neoplasms
Proteins
PLX4032
dabrafenib
Therapeutics

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Watson, I. R., Li, L., Cabeceiras, P. K., Mahdavi, M., Gutschner, T., Genovese, G., ... Chin, L. (2014). The RAC1 P29S hotspot mutation in melanoma confers resistance to pharmacological inhibition of RAF. Cancer Research, 74(17), 4845-4852. https://doi.org/10.1158/0008-5472.CAN-14-1232-T

The RAC1 P29S hotspot mutation in melanoma confers resistance to pharmacological inhibition of RAF. / Watson, Ian R.; Li, Liren; Cabeceiras, Peter K.; Mahdavi, Mozhdeh; Gutschner, Tony; Genovese, Giannicola; Wang, Guocan; Fang, Zhuangna; Tepper, James M.; Stemke-Hale, Katherine; Tsai, Kenneth Y.; Davies, Michael A.; Mills, Gordon; Chin, Lynda.

In: Cancer Research, Vol. 74, No. 17, 01.09.2014, p. 4845-4852.

Research output: Contribution to journalArticle

Watson, IR, Li, L, Cabeceiras, PK, Mahdavi, M, Gutschner, T, Genovese, G, Wang, G, Fang, Z, Tepper, JM, Stemke-Hale, K, Tsai, KY, Davies, MA, Mills, G & Chin, L 2014, 'The RAC1 P29S hotspot mutation in melanoma confers resistance to pharmacological inhibition of RAF', Cancer Research, vol. 74, no. 17, pp. 4845-4852. https://doi.org/10.1158/0008-5472.CAN-14-1232-T
Watson IR, Li L, Cabeceiras PK, Mahdavi M, Gutschner T, Genovese G et al. The RAC1 P29S hotspot mutation in melanoma confers resistance to pharmacological inhibition of RAF. Cancer Research. 2014 Sep 1;74(17):4845-4852. https://doi.org/10.1158/0008-5472.CAN-14-1232-T
Watson, Ian R. ; Li, Liren ; Cabeceiras, Peter K. ; Mahdavi, Mozhdeh ; Gutschner, Tony ; Genovese, Giannicola ; Wang, Guocan ; Fang, Zhuangna ; Tepper, James M. ; Stemke-Hale, Katherine ; Tsai, Kenneth Y. ; Davies, Michael A. ; Mills, Gordon ; Chin, Lynda. / The RAC1 P29S hotspot mutation in melanoma confers resistance to pharmacological inhibition of RAF. In: Cancer Research. 2014 ; Vol. 74, No. 17. pp. 4845-4852.
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abstract = "Following mutations in BRAF and NRAS, the RAC1 c.85C>T single-nucleotide variant (SNV) encoding P29S amino acid change represents the next most frequently observed protein-coding hotspot mutation in melanoma. However, the biologic and clinical significance of the RAC1 P29S somatic mutation in approximately 4{\%} to 9{\%} of patients remains unclear. Here, we demonstrate that melanoma cell lines possessing the RAC1 hotspot variant are resistant to RAF inhibitors (vemurafenib and dabrafenib). Enforced expression of RAC1 P29S in sensitive BRAFmutant melanoma cell lines confers resistance manifested by increased viability, decreased apoptosis, and enhanced tumor growth in vivo upon treatment with RAF inhibitors. Conversely, RNAi-mediated silencing of endogenous RAC1 P29S in a melanoma cell line with a co-occurring BRAF V600 mutation increased sensitivity to vemurafenib and dabrafenib. Our results suggest RAC1 P29S status may offer a predictive biomarker for RAF inhibitor resistance in melanoma patients, where it should be evaluated clinically.",
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