sar405838 and Colorectal-Neoplasms

There are currently no effective targeted therapies for KRAS mutant cancers. Therapeutic strategies that combine MEK inhibitors with agents that target apoptotic pathways may be a promising therapeutic approach. We investigated combining MEK and MDM2 inhibitors as a potential treatment strategy for KRAS mutant non-small cell lung cancers (NSCLC) and colorectal carcinomas that harbor wild-type TP53. The combination of pimasertib (MEK inhibitor) and SAR405838 (MDM2 inhibitor) was synergistic and induced the expression of PUMA and BIM, led to apoptosis and growth inhibition in vitro, and tumor regression in vivo. Acquired resistance to the combination commonly resulted from the acquisition of TP53 mutations, conferring complete resistance to MDM2 inhibition. In contrast, resistant clones exhibited marked variability in sensitivity to MEK inhibition, which significantly impacted sensitivity to subsequent treatment with alternative MEK inhibitor-based combination therapies. These results highlight both the potential promise and limitations of combining MEK and MDM2 inhibitors for treatment of KRAS mutant NSCLC and colorectal cancers.

Topics: A549 Cells; Animals; Apoptosis; Apoptosis Regulatory Proteins; Bcl-2-Like Protein 11; Carcinoma, Non-Small-Cell Lung; Cell Proliferation; Colorectal Neoplasms; Drug Resistance, Neoplasm; Drug Synergism; Gene Knockdown Techniques; HCT116 Cells; Humans; Indoles; Lung Neoplasms; MAP Kinase Kinase Kinases; MAP Kinase Signaling System; Mice; Mice, Nude; Mutation; Niacinamide; Protein Kinase Inhibitors; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-mdm2; Proto-Oncogene Proteins p21(ras); RNA Interference; RNA, Small Interfering; Spiro Compounds; Tumor Suppressor Protein p53; Xenograft Model Antitumor Assays