azd-6244 and Microsatellite-Instability

We analyzed responsiveness of KRAS-mutated CRC cell lines with distinctive MSI status against mitogen-activated protein kinase (MEK) inhibitor (selumetinib; AZD) and/or B-raf proto-oncogene (BRAF) kinase inhibitor (vemurafenib; PLX). The viability of MSI-high (MSI-H) KRAS-mutated LS174T cells treated with AZD or PLX was 24.5 ± 0.9% or 71.4 ± 3.6%, respectively, and the viability of microsatellite stable (MSS) KRAS-mutated SW480 cells for AZD or PLX was 57.4 ± 3.1% or 43.1 ± 1.8%, respectively. These observations imply that the therapeutic efficacy of MEK kinase inhibitors or BRAF kinase inhibitors against KRAS-mutated colon cancer cells may differ between MSI-H and MSS. However, a combination of both inhibitors synergistically inhibits the proliferation of KRAS-mutated colon cancer cells regardless of MSI status. The underlying synergistic cytotoxic efficacy of AZD/PLX combination on KRAS-mutated colon cancer cells with different MSI status was further substantiated by markedly decreased phosphorylation of ERK in both LS74T and SW480 cell lines upon AZD and PLX treatment. Based on these collective data, we propose that MSI status should be considered when MEK kinase inhibitor or BRAF kinase inhibitor is treated for KRAS-mutated colon cancer, and that combination of both inhibitors synergistically inhibit proliferation of KRAS-mutated colon cancer cells independent of MSI status.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Cell Line, Tumor; Cell Proliferation; Cell Survival; Colonic Neoplasms; Humans; MAP Kinase Kinase Kinases; Microsatellite Instability; Proto-Oncogene Mas; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins p21(ras); Vemurafenib