Abstract 4541: Dual targeting of CDK4 and MEK as a combination treatment strategy for metastatic colorectal cancer

Aberrant hyperactivation of KRAS plays a prominent role in tumor initiation and progression of a broad spectrum of human malignancies. The incidence of KRAS mutations is especially high in colorectal cancers, where it occurs at a frequency of roughly 50%. The present study addresses the hypothesis that dual targeting of CDK4 and MEK represents a viable treatment strategy for the subpopulation of colorectal cancers exhibiting hyperactivated KRAS signaling. We have generated both in vitro and in vivo data in highly passaged colorectal xenograft models to provide compelling support for further exploration of this combination treatment strategy. We have now turned to the study of primary human models that are anticipated to be more predictive of ultimate clinical activity in patients. A heterogeneous panel of low passage colorectal patient-derived xenografts (PDX) has been established from biospecimens procured during patient surgeries conducted at our institution (n=12). All xenograft models have been genomically profiled and their histologies mimicked those observed in the original samples. As anticipated, approximately half of these models harbor an oncogenic KRAS mutation and exhibit widely differing histologies, consistent with the heterogeneity encountered in the clinic. Immunoblotting analysis has further revealed that that the majority (>80%) are positive for both phosphorylated RB and constitutive pERK expression and are therefore candidates for treatment regimens combining inhibitors of CDK4 and MEK. Employing the CDK4 inhibitor palbociclib and multiple MEK inhibitors, in vivo efficacy studies are ongoing against our colorectal PDX panel. Preliminary data have shown a higher frequency of regressions in the combination arm compared to either single agent arm at the respective maximum tolerated doses. Our results therefore suggest that combined inhibition of CDK4 and MEK may provide an attractive therapeutic strategy for the treatment of colorectal cancer. Citation Format: Elizabeth Ziemke, Joseph Dosch, Amrith Shettigar, Shanshan Wan, Theodore Welling, Karin Hardiman, Judith Sebolt-Leopold. Dual targeting of CDK4 and MEK as a combination treatment strategy for metastatic colorectal cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4541. doi:10.1158/1538-7445.AM2014-4541