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

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

Research output: Contribution to journalArticlepeer-review

59 Citations (Scopus)

Abstract

Melanoma is a recalcitrant disease. The present study used a patient-derived orthotopic xenograft (PDOX) model of melanoma to test sensitivity to three molecularlytargeted 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.

Original languageEnglish
Pages (from-to)71737-71743
Number of pages7
JournalOncotarget
Volume7
Issue number44
DOIs
Publication statusPublished - 2016
Externally publishedYes

Keywords

  • Drug-response
  • Melanoma
  • Nude mice
  • Orthotopic
  • PDOX

ASJC Scopus subject areas

  • Oncology

Fingerprint Dive into the research topics of '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'. Together they form a unique fingerprint.

Cite this