Mouse tumor susceptibility genes identify drug combinations for multiple myeloma.

Long-term genetic studies utilizing backcross and congenic strain analyses coupled with positional cloning strategies and functional studies identified , , and as mouse plasmacytoma susceptibility/resistance genes. Tumor incidence data in congenic strains carrying the resistance alleles of and led us to hypothesize that drug combinations affecting these pathways are likely to have an additive, if not synergistic effect in inhibiting tumor cell growth. Traditional and novel systems-level genomic approaches were used to assess combination activity, disease specificity, and clinical potential of a drug combination involving rapamycin/everolimus, an inhibitor, with entinostat, an histone deacetylase inhibitor. The combination synergistically repressed oncogenic and activated the tumor suppressor. The identification of as a primary upstream regulator led to the identification of small molecule binders of the G-quadruplex structure that forms in the NHEIII region of the promoter. These studies highlight the importance of identifying drug combinations which simultaneously upregulate tumor suppressors and downregulate oncogenes.