trametinib and Colorectal-Neoplasms

KRAS, the most common oncogenic driver in human cancers, is controlled and signals primarily through protein-protein interactions (PPIs). The interaction between KRAS and SOS1, crucial for the activation of KRAS, is a typical, challenging PPI with a large contact surface area and high affinity. Here, we report that the addition of only one atom placed between Y884

Topics: Afatinib; Allosteric Regulation; Binding Sites; Catalytic Domain; Colorectal Neoplasms; ErbB Receptors; Humans; Molecular Dynamics Simulation; Mutagenesis, Site-Directed; Protein Interaction Maps; Proto-Oncogene Proteins p21(ras); Quinazolines; SOS1 Protein

The MAPK pathway is one of the most important pathways for novel anticancer drug development. We performed high-throughput screening for compounds that induce expression of p15INK4b, and identified JTP-74057 (GSK1120212), which is being evaluated in ongoing phase I, II and III clinical trials. We characterized its antitumor activities in vitro and in vivo. JTP-74057 strongly inhibited MEK1/2 kinase activities, but did not inhibit another 98 kinase activities. Treatment by JTP-74057 resulted in growth inhibition accompanied with upregulation of p15INK4b and/or p27KIP1 in most of the colorectal cancer cell lines tested. Daily oral administration of JTP-74057 for 14 days suppressed tumor growth of HT-29 and COLO205 xenografts in nude mice. Notably, tumor regression was observed only in COLO205 xenografts, and COLO205 was much more sensitive to JTP-74057-induced apoptosis than HT-29 in vitro. Treatment with an Akt inhibitor enhanced the JTP-74057-induced apoptosis in HT-29 cells. Finally, JTP-74057 exhibited an additive or a synergistic effect in combination with the standard-of-care agents, 5-fluorouracil, oxaliplatin or SN-38. JTP-74057, a highly specific and potent MEK1/2 inhibitor, exerts favorable antitumor activities in vitro and in vivo. Sensitivity to JTP-74057-induced apoptosis may be an important factor for the estimation of in vivo efficacy, and sensitivity was enhanced by an Akt inhibitor. These results suggest the usefulness of JTP-74057 in therapeutic applications for colorectal cancer patients.

Topics: Animals; Antimetabolites, Antineoplastic; Apoptosis; Cell Line, Tumor; Cell Proliferation; Colorectal Neoplasms; Drug Synergism; Female; Fluorouracil; HCT116 Cells; HT29 Cells; Humans; MAP Kinase Kinase 1; MAP Kinase Kinase 2; Mice; Mice, Inbred BALB C; Mice, Nude; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Xenograft Model Antitumor Assays