MEK inhibitor trametinib in combination with gemcitabine regresses a patient-derived orthotopic xenograft (PDOX) pancreatic cancer nude mouse model

Author:

Kawaguchi, Kei

Igarashi, Kentaro

Miyake, Kentaro

Lwin, Thinzar M

Miyake, Masuyo

Kiyuna, Tasuku

Hwang, Ho Kyoung

Murakami, Takashi

Delong, Jonathan C

Singh, Shree Ram

Clary, Bryan

Bouvet, Michael

Unno, Michiaki

Hoffman, Robert M
Author Address

AntiCancer, Inc., 7917 Ostrow Street, San Diego, CA, 92111, USA; Department of Surgery, University of California, San Diego, CA, 92093, USA; Department of Surgery, Graduate School of Medicine, Tohoku University, Sendai, 980-8574, Japan., AntiCancer, Inc., 7917 Ostrow Street, San Diego, CA, 92111, USA; Department of Surgery, University of California, San Diego, CA, 92093, USA., Basic Research Laboratory, National Cancer Institute, Frederick, MD, 21702, USA. Electronic address: singhshr@mail.nih.gov., Department of Surgery, University of California, San Diego, CA, 92093, USA. Electronic address: bclary@ucsd.edu., Department of Surgery, University of California, San Diego, CA, 92093, USA. Electronic address: mbouvet@ucsd.edu., Department of Surgery, Graduate School of Medicine, Tohoku University, Sendai, 980-8574, Japan. Electronic address: m_unno@surg1.med.tohoku.ac.jp., AntiCancer, Inc., 7917 Ostrow Street, San Diego, CA, 92111, USA; Department of Surgery, University of California, San Diego, CA, 92093, USA. Electronic address: all@anticancer.com.,

Abstract:

Pancreatic cancer is resistant to treatment and needs precision individualized therapy to improve the outcome of this disease. Previously, we demonstrated that trametinib (TRA), a MEK inhibitor, could inhibit a pancreatic cancer patient-derived orthotopic xenograft (PDOX). In the present study, we show that gemcitabine (GEM) in combination with TRA was more effective than TRA alone. We implanted a patient pancreatic cancer orthotopically in the pancreatic tail of nude mice to establish the PDOX model. After seven weeks of tumor growth, we divided 32 pancreatic-cancer PDOX nude mice into 4 groups of eight: untreated control; GEM (once a week for 2 weeks); TRA (14 consecutive days); GEM?+?TRA (GEM: once a week for 2 weeks, TRA:14 consecutive days). We found that treated mice on day 14 had significantly reduced tumor volume in comparison to untreated control. TRA and the combination of GEM?+?TRA therapy significantly inhibited tumor development in comparison to GEM alone. However, GEM?+?TRA inhibited the PDOX tumor growth significantly greater than TRA alone. These results suggest the clinical potential of the combination of TRA and GEM for pancreatic cancer. Published by Elsevier Ltd.

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