Vemurafenib-resistant BRAF-V600E-mutated melanoma is regressed by MEK-targeting drug trametinib, but not cobimetinib in a patient-derived orthotopic xenograft (PDOX) mouse model.

Abstract

Melanoma is a recalcitrant disease. The present study used a patient-derived orthotopic xenograft (PDOX) model of melanoma to test sensitivity to three molecularly-targeted drugs and one standard chemotherapeutic. A BRAF-V600E-mutant melanoma obtained from the right chest wall of a patient was grown orthotopically in the right chest wall of nude mice to establish a PDOX model. Two weeks after implantation, 50 PDOX nude mice were divided into 5 groups: G1, control without treatment; G2, vemurafenib (VEM) (30 mg/kg); G3; temozolomide (TEM) (25 mg/kg); G4, trametinib (TRA) (0.3 mg/kg); and G5, cobimetinib (COB) (5 mg/kg). Each drug was administered orally, daily for 14 consecutive days. Tumor sizes were measured with calipers twice a week. On day 14 from initiation of treatment, TRA, an MEK inhibitor, was the only agent of the 4 tested that caused tumor regression (P < 0.001 at day 14). In contrast, another MEK inhibitor, COB, could slow but not arrest growth or cause regression of the melanoma. First-line therapy TEM could slow but not arrest tumor growth or cause regression. The patient in this study had a BRAF-V600E-mutant melanoma and would be considered to be a strong candidate for VEM as first-line therapy, since VEM targets this mutation. However, VEM was not effective. The PDOX model thus helped identify the very-high efficacy of TRA against the melanoma PDOX and is a promising drug for this patient. These results demonstrate the powerful precision of the PDOX model for cancer therapy, not achievable by genomic analysis alone.

• Authors: Kei Kawaguchi, Takashi Murakami, Bartosz Chmielowski, Kentaro Igarashi, Tasuku Kiyuna, Michiaki Unno, Scott D Nelson, Tara A Russell, Sarah M Dry, Yunfeng Li, Fritz C Eilber, Robert M Hoffman
• Journal: Oncotarget (Oncotarget) Vol. 7 Issue 44 Pg. 71737-71743 (Nov 01 2016) ISSN: 1949-2553 [Electronic] United States
• PMID: 27690220 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Azetidines
• Indoles
• Piperidines
• Pyridones
• Pyrimidinones
• Sulfonamides
• Vemurafenib
• trametinib
• Proto-Oncogene Proteins B-raf
• Mitogen-Activated Protein Kinase Kinases
• cobimetinib

Topics

• Aged
• Animals
• Antineoplastic Agents (therapeutic use)
• Azetidines (therapeutic use)
• Drug Resistance, Neoplasm
• Female
• Humans
• Indoles (therapeutic use)
• Melanoma (drug therapy, genetics)
• Mice
• Mitogen-Activated Protein Kinase Kinases (antagonists & inhibitors)
• Mutation
• Piperidines (therapeutic use)
• Proto-Oncogene Proteins B-raf (genetics)
• Pyridones (therapeutic use)
• Pyrimidinones (therapeutic use)
• Sulfonamides (therapeutic use)
• Vemurafenib
• Xenograft Model Antitumor Assays