RAF265 inhibits the growth of advanced human melanoma tumors

Yingjun Su, Anna E. Vilgelm, Mark C. Kelley, Oriana E. Hawkins, Yan Liu, Kelli L. Boyd, Sara Kantrow, Ryan C. Splittgerber, Sarah P. Short, Tammy Sobolik, Snjezana Zaja-Milatovic, Kimberly Brown Dahlman, Katayoun I. Amiri, Aixiang Jiang, Pengcheng Lu, Yu Shyr, Darrin D. Stuart, Shawn Levy, Jeffrey A. Sosman, Ann Richmond

Research output: Contribution to journalArticle

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Abstract

Purpose: The purpose of this preclinical study was to determine the effectiveness of RAF265, a multikinase inhibitor, for treatment of human metastatic melanoma and to characterize traits associated with drug response. Experimental Design: Advanced metastatic melanoma tumors from 34 patients were orthotopically implanted to nude mice. Tumors that grew in mice (17 of 34) were evaluated for response to RAF265 (40 mg/kg, every day) over 30 days. The relation between patient characteristics, gene mutation profile, global gene expression profile, and RAF265 effects on tumor growth, mitogen-activated protein/extracellular signal-regulated kinase (MEK)/extracellular signal-regulated kinase (ERK) phosphorylation, proliferation, and apoptosis markers was evaluated. Results: Nine of the 17 tumors that successfully implanted (53%) were mutant BRAF (BRAF V600E/K), whereas eight of 17 (47%) tumors were BRAF wild type (BRAF WT). Tumor implants from 7 of 17 patients (41%) responded to RAF265 treatment with more than 50% reduction in tumor growth. Five of the 7 (71%) responders were BRAF WT, of which 1 carried c-KIT L576P and another N-RAS Q61R mutation, while only 2 (29%) of the responding tumors were BRAF V600E/K. Gene expression microarray data from nonimplanted tumors revealed that responders exhibited enriched expression of genes involved in cell growth, proliferation, development, cell signaling, gene expression, and cancer pathways. Although response to RAF265 did not correlate with pERK1/2 reduction, RAF265 responders did exhibit reduced pMEK1, reduced proliferation based upon reduced Ki-67, cyclin D1 and polo-like kinase1 levels, and induction of the apoptosis mediator BCL2-like 11. Conclusions: Orthotopic implants of patient tumors in mice may predict prognosis and treatment response for melanoma patients. A subpopulation of human melanoma tumors responds to RAF265 and can be characterized by gene mutation and gene expression profiles.

Original languageEnglish (US)
Pages (from-to)2184-2198
Number of pages15
JournalClinical Cancer Research
Volume18
Issue number8
DOIs
StatePublished - Apr 15 2012

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Melanoma
Growth
Neoplasms
Extracellular Signal-Regulated MAP Kinases
Transcriptome
Gene Expression
Mutation
RAF265
Apoptosis
Cyclin D1
Mitogen-Activated Protein Kinase Kinases
Growth and Development
Mitogens
Nude Mice
Genes
Research Design
Therapeutics
Phosphorylation
Cell Proliferation

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Su, Y., Vilgelm, A. E., Kelley, M. C., Hawkins, O. E., Liu, Y., Boyd, K. L., ... Richmond, A. (2012). RAF265 inhibits the growth of advanced human melanoma tumors. Clinical Cancer Research, 18(8), 2184-2198. https://doi.org/10.1158/1078-0432.CCR-11-1122

RAF265 inhibits the growth of advanced human melanoma tumors. / Su, Yingjun; Vilgelm, Anna E.; Kelley, Mark C.; Hawkins, Oriana E.; Liu, Yan; Boyd, Kelli L.; Kantrow, Sara; Splittgerber, Ryan C.; Short, Sarah P.; Sobolik, Tammy; Zaja-Milatovic, Snjezana; Dahlman, Kimberly Brown; Amiri, Katayoun I.; Jiang, Aixiang; Lu, Pengcheng; Shyr, Yu; Stuart, Darrin D.; Levy, Shawn; Sosman, Jeffrey A.; Richmond, Ann.

In: Clinical Cancer Research, Vol. 18, No. 8, 15.04.2012, p. 2184-2198.

Research output: Contribution to journalArticle

Su, Y, Vilgelm, AE, Kelley, MC, Hawkins, OE, Liu, Y, Boyd, KL, Kantrow, S, Splittgerber, RC, Short, SP, Sobolik, T, Zaja-Milatovic, S, Dahlman, KB, Amiri, KI, Jiang, A, Lu, P, Shyr, Y, Stuart, DD, Levy, S, Sosman, JA & Richmond, A 2012, 'RAF265 inhibits the growth of advanced human melanoma tumors', Clinical Cancer Research, vol. 18, no. 8, pp. 2184-2198. https://doi.org/10.1158/1078-0432.CCR-11-1122
Su Y, Vilgelm AE, Kelley MC, Hawkins OE, Liu Y, Boyd KL et al. RAF265 inhibits the growth of advanced human melanoma tumors. Clinical Cancer Research. 2012 Apr 15;18(8):2184-2198. https://doi.org/10.1158/1078-0432.CCR-11-1122
Su, Yingjun ; Vilgelm, Anna E. ; Kelley, Mark C. ; Hawkins, Oriana E. ; Liu, Yan ; Boyd, Kelli L. ; Kantrow, Sara ; Splittgerber, Ryan C. ; Short, Sarah P. ; Sobolik, Tammy ; Zaja-Milatovic, Snjezana ; Dahlman, Kimberly Brown ; Amiri, Katayoun I. ; Jiang, Aixiang ; Lu, Pengcheng ; Shyr, Yu ; Stuart, Darrin D. ; Levy, Shawn ; Sosman, Jeffrey A. ; Richmond, Ann. / RAF265 inhibits the growth of advanced human melanoma tumors. In: Clinical Cancer Research. 2012 ; Vol. 18, No. 8. pp. 2184-2198.
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abstract = "Purpose: The purpose of this preclinical study was to determine the effectiveness of RAF265, a multikinase inhibitor, for treatment of human metastatic melanoma and to characterize traits associated with drug response. Experimental Design: Advanced metastatic melanoma tumors from 34 patients were orthotopically implanted to nude mice. Tumors that grew in mice (17 of 34) were evaluated for response to RAF265 (40 mg/kg, every day) over 30 days. The relation between patient characteristics, gene mutation profile, global gene expression profile, and RAF265 effects on tumor growth, mitogen-activated protein/extracellular signal-regulated kinase (MEK)/extracellular signal-regulated kinase (ERK) phosphorylation, proliferation, and apoptosis markers was evaluated. Results: Nine of the 17 tumors that successfully implanted (53{\%}) were mutant BRAF (BRAF V600E/K), whereas eight of 17 (47{\%}) tumors were BRAF wild type (BRAF WT). Tumor implants from 7 of 17 patients (41{\%}) responded to RAF265 treatment with more than 50{\%} reduction in tumor growth. Five of the 7 (71{\%}) responders were BRAF WT, of which 1 carried c-KIT L576P and another N-RAS Q61R mutation, while only 2 (29{\%}) of the responding tumors were BRAF V600E/K. Gene expression microarray data from nonimplanted tumors revealed that responders exhibited enriched expression of genes involved in cell growth, proliferation, development, cell signaling, gene expression, and cancer pathways. Although response to RAF265 did not correlate with pERK1/2 reduction, RAF265 responders did exhibit reduced pMEK1, reduced proliferation based upon reduced Ki-67, cyclin D1 and polo-like kinase1 levels, and induction of the apoptosis mediator BCL2-like 11. Conclusions: Orthotopic implants of patient tumors in mice may predict prognosis and treatment response for melanoma patients. A subpopulation of human melanoma tumors responds to RAF265 and can be characterized by gene mutation and gene expression profiles.",
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AU - Su, Yingjun

AU - Vilgelm, Anna E.

AU - Kelley, Mark C.

AU - Hawkins, Oriana E.

AU - Liu, Yan

AU - Boyd, Kelli L.

AU - Kantrow, Sara

AU - Splittgerber, Ryan C.

AU - Short, Sarah P.

AU - Sobolik, Tammy

AU - Zaja-Milatovic, Snjezana

AU - Dahlman, Kimberly Brown

AU - Amiri, Katayoun I.

AU - Jiang, Aixiang

AU - Lu, Pengcheng

AU - Shyr, Yu

AU - Stuart, Darrin D.

AU - Levy, Shawn

AU - Sosman, Jeffrey A.

AU - Richmond, Ann

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N2 - Purpose: The purpose of this preclinical study was to determine the effectiveness of RAF265, a multikinase inhibitor, for treatment of human metastatic melanoma and to characterize traits associated with drug response. Experimental Design: Advanced metastatic melanoma tumors from 34 patients were orthotopically implanted to nude mice. Tumors that grew in mice (17 of 34) were evaluated for response to RAF265 (40 mg/kg, every day) over 30 days. The relation between patient characteristics, gene mutation profile, global gene expression profile, and RAF265 effects on tumor growth, mitogen-activated protein/extracellular signal-regulated kinase (MEK)/extracellular signal-regulated kinase (ERK) phosphorylation, proliferation, and apoptosis markers was evaluated. Results: Nine of the 17 tumors that successfully implanted (53%) were mutant BRAF (BRAF V600E/K), whereas eight of 17 (47%) tumors were BRAF wild type (BRAF WT). Tumor implants from 7 of 17 patients (41%) responded to RAF265 treatment with more than 50% reduction in tumor growth. Five of the 7 (71%) responders were BRAF WT, of which 1 carried c-KIT L576P and another N-RAS Q61R mutation, while only 2 (29%) of the responding tumors were BRAF V600E/K. Gene expression microarray data from nonimplanted tumors revealed that responders exhibited enriched expression of genes involved in cell growth, proliferation, development, cell signaling, gene expression, and cancer pathways. Although response to RAF265 did not correlate with pERK1/2 reduction, RAF265 responders did exhibit reduced pMEK1, reduced proliferation based upon reduced Ki-67, cyclin D1 and polo-like kinase1 levels, and induction of the apoptosis mediator BCL2-like 11. Conclusions: Orthotopic implants of patient tumors in mice may predict prognosis and treatment response for melanoma patients. A subpopulation of human melanoma tumors responds to RAF265 and can be characterized by gene mutation and gene expression profiles.

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