TY - JOUR
T1 - RAF265 inhibits the growth of advanced human melanoma tumors
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
PY - 2012/4/15
Y1 - 2012/4/15
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.
AB - 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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U2 - 10.1158/1078-0432.CCR-11-1122
DO - 10.1158/1078-0432.CCR-11-1122
M3 - Article
C2 - 22351689
AN - SCOPUS:84859873585
SN - 1078-0432
VL - 18
SP - 2184
EP - 2198
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 8
ER -