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Published on: July 8, 2020
RAF265 inhibits the growth of advanced human melanoma tumors
Yingjun Su1, Anna E Vilgelm, Mark C Kelley
1Department of Veterans Affairs, Vanderbilt-Ingram Cancer Center and Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
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.
Insights
RAF265, a multikinase inhibitor, showed effectiveness in treating a subset of human metastatic melanoma tumors. Patient tumor implants in mice can predict response to RAF265, which is linked to specific gene profiles.
Area of Science:
- Oncology
- Pharmacology
- Genetics
Background:
- Metastatic melanoma is a significant health concern with limited treatment options.
- RAF265 is a multikinase inhibitor investigated for its therapeutic potential.
Purpose of the Study:
- To evaluate the efficacy of RAF265 in treating human metastatic melanoma.
- To identify characteristics associated with patient response to RAF265 treatment.
Main Methods:
- Orthotopic implantation of advanced human metastatic melanoma tumors into nude mice.
- Evaluation of RAF265 treatment response (40 mg/kg daily for 30 days) in 17 successful tumor implants.
- Analysis of patient characteristics, gene mutation profiles, gene expression, and molecular markers of tumor growth, proliferation, and apoptosis.
Main Results:
- 41% of implanted tumors (7 of 17) responded to RAF265 with >50% tumor growth reduction.
- Responders were predominantly BRAF wild-type (71%), with some carrying c-KIT or N-RAS mutations.
- Responders showed reduced proliferation (Ki-67, cyclin D1, PLK1) and induced apoptosis (BCL2L11), but not reduced pERK1/2; reduced pMEK1 was observed.
Conclusions:
- Orthotopic patient-derived xenografts in mice can predict melanoma prognosis and treatment response.
- A distinct subpopulation of human melanoma tumors responds to RAF265, identifiable through gene mutation and expression profiling.
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