Oncotarget

Research Papers:

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 and Robert M. Hoffman _

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Oncotarget. 2016; 7:71737-71743. https://doi.org/10.18632/oncotarget.12328

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Abstract

Kei Kawaguchi1,2,3, Takashi Murakami1,2, Bartosz Chmielowski4, Kentaro Igarashi1,2, Tasuku Kiyuna1,2, Michiaki Unno3, Scott D. Nelson5, Tara A. Russell6, Sarah M. Dry5, Yunfeng Li5, Fritz C. Eilber6, Robert M. Hoffman1,2

1AntiCancer Inc., San Diego, CA, USA

2Department of Surgery, University of California, San Diego, CA, USA

3Department of Surgery, Graduate School of Medicine, Tohoku University, Sendai, Japan

4Division of Hematology-Oncology, University of California, Los Angeles, CA, USA

5Department of Pathology, University of California, Los Angeles, CA, USA

6Division of Surgical Oncology, University of California, Los Angeles, CA, USA

Correspondence to:

Robert M. Hoffman, email: all@anticancer.com

Fritz C. Eilber, email: fceilber@mednet.ucla.edu

Keywords: melanoma, PDOX, nude mice, orthotopic, drug-response

Received: July 26, 2016     Accepted: September 20, 2016     Published: September 28, 2016

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.


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