Analysis Of The Combinatorial Antiproliferative Effect Of Pan Raf Inhibitor Az-628 And Mek1-Inhibitor Azd-6244 On A Large Panel Of Tumor Cell Lines

Cancer is a highly complex, multigenic disease with tumor cells underlying constant transition. Single drug treatments against specific targets frequently result in only partial success because mutations and redundant pathways cause drug resistance. Therefore, drug combinations that effect different synergistically acting targets in the cancer cell in parallel have become a promising strategy to improve the success in many fields of cancer therapy. One example for such an approach is the co-treatment of B-Raf driven tumors with Raf and MEK1 inhibitors. In our study, we determined the combinatorial effect of the pan-Raf inhibitor AZ-628 and the MEK1 inhibitor AZD-6244 on the viability of a large panel of more than 100 tumor cell lines. Whittaker et al. (Mol.CancerTher, 2015) could already show that this drug combination has a significant synergistic effect in several melanoma and colon cancer cell lines. The authors showed evidence that synergistic activity was correlated with enhanced mutation-triggered RAS/RAF/MAPK signaling with a special role for C-Raf in resistance due to a negative feedback mechanism. We here applied the combination of AZD-6244 and AZ-628 in a broad checkerboard pattern to a multitude of cell lines from other entities beyond melanoma and colorectal cancer. Based on these results we correlated the observed synergistic and non-synergistic effects with gene expression profiles of these cell lines and analyzed the requirement of a MAPK activating signaling. Our approach revealed that synergistic activity is not confined to melanoma and colon cancer but is observed in tumors from other entities as well. This observation may expand the usefulness of MEK/Raf inhibitor co-treatment to a larger panel of cancer types. Citation Format: Alokta Chakrabarti, Daniel Feger, Sarah Umber, Orysya Stus, Marianne Birkle, Oliver Siedentopf, Jan E. Ehlert. Analysis of the combinatorial antiproliferative effect of pan RAF inhibitor AZ-628 and MEK1-inhibitor AZD-6244 on a large panel of tumor cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1208. doi:10.1158/1538-7445.AM2017-1208