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.
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.
AntiCancer Inc., San Diego, CA, USA.|Department of Surgery, University of California, San Diego, CA, USA.|Department of Surgery, Graduate School of Medicine, Tohoku University, Sendai, Japan.
Kei
K
Kawaguchi
AntiCancer Inc., San Diego, CA, USA.|Department of Surgery, University of California, San Diego, CA, USA.
Takashi
T
Murakami
Division of Hematology-Oncology, University of California, Los Angeles, CA, USA.
Bartosz
B
Chmielowski
AntiCancer Inc., San Diego, CA, USA.|Department of Surgery, University of California, San Diego, CA, USA.
Kentaro
K
Igarashi
AntiCancer Inc., San Diego, CA, USA.|Department of Surgery, University of California, San Diego, CA, USA.
Tasuku
T
Kiyuna
Department of Surgery, Graduate School of Medicine, Tohoku University, Sendai, Japan.
Michiaki
M
Unno
Department of Pathology, University of California, Los Angeles, CA, USA.
Scott D
SD
Nelson
Division of Surgical Oncology, University of California, Los Angeles, CA, USA.
Tara A
TA
Russell
Department of Pathology, University of California, Los Angeles, CA, USA.
Sarah M
SM
Dry
Department of Pathology, University of California, Los Angeles, CA, USA.
Yunfeng
Y
Li
Division of Surgical Oncology, University of California, Los Angeles, CA, USA.
Fritz C
FC
Eilber
AntiCancer Inc., San Diego, CA, USA.|Department of Surgery, University of California, San Diego, CA, USA.
Robert M
RM
Hoffman
D000368:Aged; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001384:Azetidines / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D007211:Indoles / Q000627:therapeutic use*; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors*; D009154:Mutation; D010880:Piperidines / Q000627:therapeutic use*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D011728:Pyridones / Q000627:therapeutic use*; D011744:Pyrimidinones / Q000627:therapeutic use*; D013449:Sulfonamides / Q000627:therapeutic use*; D000077484:Vemurafenib; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D001384:Azetidines; D007211:Indoles; D010880:Piperidines; D011728:Pyridones; D011744:Pyrimidinones; D013449:Sulfonamides; D000077484:Vemurafenib; C560077:trametinib; D048493:Proto-Oncogene Proteins B-raf; D020929:Mitogen-Activated Protein Kinase Kinases; C574276:cobimetinib
PDOX; drug-response; melanoma; nude mice; orthotopic
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