In vivo antitumor growth efficacy of BI-847325 in combination with capecitabine. Combinations (simultaneously or sequentially) were compared with both monotherapies. A, Tumor growth curves are represented as the relative tumor volume (%) over time (days). Black curves: control vehicle 10 mL/kg/day on days 1–7. Blue curves: BI-847325 administered at 80 mg/kg/day on days 1, 8, and 15. Green curves: capecitabine 150 mg/kg/day on days 1–7. Red curves: BI-847325 administered at 80 mg/kg/day on days 1, 8, and 15 (h:1), plus capecitabine administered at 150 mg/kg/day on days 1–7 (h:0). Purple curves: capecitabine 150 mg/kg/day on day 1–7 plus BI-847325 80 mg/kg/day on days 8, 15, and 22. CXF 1103, colorectal cancer; GXA 3011 and GXA 3023, gastric cancer; MAXFTN 401, triple-negative mammary cancer. B, T/C values (%), relative tumor volume (RTV, %), and synergism index based on RTV. Rating of BI-847325 antitumor activity is defined in the Materials and Methods section.
ARTICLE ABSTRACTBI-847325 is an ATP-competitive inhibitor of MEK/Aurora kinases with the potential to treat a wide range of cancers. In a panel of 294 human tumor cell lines in vitro, BI-847325 was found to be a highly selective inhibitor that was active in the submicromolar range. The most sensitive cancer types were acute lymphocytic and myelocytic leukemia, melanomas, bladder, colorectal, and mammary cancers. BI-847325 showed a broader range of activity than the MEK inhibitor GDC-0623. The high efficacy of BI-847325 was associated with but not limited to cell lines with oncogenic mutations in NRAS, BRAF, and MAP2K1.The high antiproliferative activity of BI-847325 was validated in vivo using subcutaneous xenograft models. After oral administration of 80 and 40 mg/kg once weekly for 3 or 4 weeks, BI-847325 was highly active in four of five colorectal, two of two gastric, two of two mammary, and one of one pancreatic cancer models (test/control < 25%), and tumor regressions were observed in five of 11 cancer models. The treatment was well tolerated with no relevant lethality or body weight changes. In combination with capecitabine, BI-847325 displayed synergism over single-agent therapies, leading to complete remission in the triple-negative mammary model MAXFTN 401, partial regression in the colon model CXF 1103, and stasis in the gastric models GXA 3011 and GXA 3023. In conclusion, dual MEK/Aurora kinase inhibition shows remarkable potential for treating multiple types of hematologic and solid tumors. The combination with capecitabine was synergistic in colorectal, gastric, and mammary cancer.
We report the preclinical evaluation of BI-847325, a MEK/Aurora kinase inhibitor. Our data demonstrate that BI-847325 has potent antitumor activity in a broad range of human solid and hematologic cancer models in vitro and in vivo and is well tolerated in animal models. It also shows synergistic effect when combined with capecitabine. These findings provide a strong rationale for further development of BI-847325 as a potential therapeutic for patients with cancer.