MEK162 enhances antitumor activity of 5-fluorouracil and trifluridine in KRAS-mutated human colorectal cancer cell lines

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.