Jun Gong1, Yuan Chen2, Lixin Yang3, Raju Pillai3, Senji Shirasawa4, Marwan Fakih5. 1. Department of Medical Oncology, City of Hope National Medical Center, Duarte, CA, U.S.A. 2. Department of Molecular Medicine, City of Hope National Medical Center, Duarte, CA, U.S.A. 3. Department of Pathology, City of Hope National Medical Center, Duarte, CA, U.S.A. 4. Department of Cell Biology, Faculty of Medicine, Fukuoka University, Fukuoka, Japan. 5. Medical Oncology and Experimental Therapeutics, City of Hope Comprehensive Cancer Center, Duarte, CA, U.S.A. mfakih@coh.org.
Abstract
BACKGROUND: Preclinical evidence demonstrates that mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway inhibition increases sensitivity to 5-fluorouracil (5-FU) in colorectal cancer (CRC) cell lines and xenografts. Here, we aimed to investigate how CRC cell sensitivity to this combination is correlated to Kirsten rat sarcoma (KRAS) and proto-oncogene B-rapidly accelerated fibrosarcoma (BRAF) mutation, that are common in CRC and often lead to resistance to chemotherapy. MATERIALS AND METHODS: Wild-type and mutant KRAS/BRAF human CRC cell lines were treated with escalating doses of 5-FU or trifluridine with MEK162 (MEK1/2 inhibitor) for 72 h. Cell viability was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and synergism expressed by the combination index was calculated using CalcuSyn. RESULTS: Evidence of synergistic antitumor activity was observed for the majority of human CRC cell lines treated with MEK162 plus 5-FU (4/6) or trifluridine (7/9). Synergism was greater in KRAS- or BRAF-mutant cell lines compared to wild-type KRAS/BRAF CRC cell lines. CONCLUSION: The combination of MEK inhibition and trifluridine is worthwhile advancing in clinical development, particularly for treatment-refractory KRAS- or BRAF-mutated metastatic CRC. Copyright
BACKGROUND: Preclinical evidence demonstrates that mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway inhibition increases sensitivity to 5-fluorouracil (5-FU) in colorectal cancer (CRC) cell lines and xenografts. Here, we aimed to investigate how CRC cell sensitivity to this combination is correlated to Kirsten rat sarcoma (KRAS) and proto-oncogene B-rapidly accelerated fibrosarcoma (BRAF) mutation, that are common in CRC and often lead to resistance to chemotherapy. MATERIALS AND METHODS: Wild-type and mutant KRAS/BRAF human CRC cell lines were treated with escalating doses of 5-FU or trifluridine with MEK162 (MEK1/2 inhibitor) for 72 h. Cell viability was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and synergism expressed by the combination index was calculated using CalcuSyn. RESULTS: Evidence of synergistic antitumor activity was observed for the majority of human CRC cell lines treated with MEK162 plus 5-FU (4/6) or trifluridine (7/9). Synergism was greater in KRAS- or BRAF-mutant cell lines compared to wild-type KRAS/BRAF CRC cell lines. CONCLUSION: The combination of MEK inhibition and trifluridine is worthwhile advancing in clinical development, particularly for treatment-refractory KRAS- or BRAF-mutated metastatic CRC. Copyright
Authors: Justin Guinney; Charles Ferté; Jonathan Dry; Robert McEwen; Gilles Manceau; K J Kao; Kai-Ming Chang; Claus Bendtsen; Kevin Hudson; Erich Huang; Brian Dougherty; Michel Ducreux; Jean-Charles Soria; Stephen Friend; Jonathan Derry; Pierre Laurent-Puig Journal: Clin Cancer Res Date: 2013-10-29 Impact factor: 12.531
Authors: Giorgia Migliardi; Francesco Sassi; Davide Torti; Francesco Galimi; Eugenia R Zanella; Michela Buscarino; Dario Ribero; Andrea Muratore; Paolo Massucco; Alberto Pisacane; Mauro Risio; Lorenzo Capussotti; Silvia Marsoni; Federica Di Nicolantonio; Alberto Bardelli; Paolo M Comoglio; Livio Trusolino; Andrea Bertotti Journal: Clin Cancer Res Date: 2012-03-05 Impact factor: 12.531
Authors: Shi Yu Yang; Anur Miah; Kevin M Sales; Barry Fuller; Alexander M Seifalian; Marc Winslet Journal: Int J Oncol Date: 2011-03-21 Impact factor: 5.650
Authors: Richard M Goldberg; Daniel J Sargent; Roscoe F Morton; Charles S Fuchs; Ramesh K Ramanathan; Stephen K Williamson; Brian P Findlay; Henry C Pitot; Steven R Alberts Journal: J Clin Oncol Date: 2003-12-09 Impact factor: 44.544
Authors: Irene V Bijnsdorp; Godefridus J Peters; Olaf H Temmink; Masakazu Fukushima; Frank A Kruyt Journal: Int J Cancer Date: 2010-05-15 Impact factor: 7.396
Authors: Diane M Pereira; André E S Simões; Sofia E Gomes; Rui E Castro; Tânia Carvalho; Cecília M P Rodrigues; Pedro M Borralho Journal: Oncotarget Date: 2016-06-07
Authors: Dipanjan Basu; Cláudia M Salgado; Bruce Bauer; Yasmin Khakoo; Janki R Patel; Ryan M Hoehl; Dominique M Bertolini; Joie Zabec; Morgan R Brzozowski; Miguel Reyes-Múgica Journal: Cancer Genomics Proteomics Date: 2018 Jul-Aug Impact factor: 4.069