Abstract 5161: Inhibition of TBK1/IKBKE impacts tumor growth of KRAS-mutant colorectal cancers

Mutations in RAS occur in an estimated one third of all human cancers.  While direct targeting of RAS remains challenging, targeting downstream RAS effector molecules has been shown to impact the oncogenic function of RAS and elicit anti-tumor activity.  TANK Binding Kinase 1 (TBK1) and I-Kappa B Kinase Epsilon (IKBKE) serine/threonine kinases are non-canonical IKK family members. TBK1 is directly downstream of the RAS effector Ral Guanine Nucleotide Dissociation Stimulator (RALGDS) and may be required for RAS to elicit its full oncogenic potential.  To explore this possibility, we identified a potent and selective TBK1/IKBKE inhibitor to determine whether inhibition of TBK1 impacts the growth of RAS-mutant cancer models. KRAS-mutant cancer cell lines showed preferential sensitivity to TBK1/IKBKE inhibition over KRAS wild-type cell lines.  The TBK1/IKBKE inhibitor was then evaluated in vivo with two KRAS-mutant colorectal cancer patient-derived xenograft (PDX) models, one of which harbors co-occurring PIK3CA and KRAS mutations. The TBK1/IKBKE inhibitor caused moderate tumor growth inhibition in comparison to vehicle in both PDX models.  Since RAS exerts its oncogenic effects via additional effectors, such as RAF, and that inhibition of MEK1/2 resulted in compensatory activation of TBK1 in a KRAS-mutant cancer cell line, we tested if inhibition of TBK1/IKBKE in combination with the MEK inhibitor, trametinib, would result in superior efficacy in PDX models.  The combination of a TBK1/IKBKE inhibitor and trametinib resulted in greater than 90% tumor growth inhibition within both of these KRAS mutant PDX models compared to either single agent alone.  We also tested TBK1/IKBKE inhibition in a KRAS wild-type colorectal PDX model containing a BRAF mutation. In this model, TBK1/IKBKE did not inhibit tumor growth and, although there was significant tumor growth inhibition with trametinib alone, there was no further enhancement of efficacy with the addition of a TBK1/IKBKE inhibitor. Together, these data suggest that a TBK1/IKBKE inhibitor in combination with a MEK inhibitor may impact KRAS-mutant cancers. Citation Format: Susanna Stinson, Jianhua He, Zhiheng Jia, Katie S. Walker, Zhi-Hua Cui, Joshua A. Kaplan, Chandrasekar Venkataramani, Yujin Wang, Fatima Guevara, Timothy Nelson, Ewa Sicinska, Kimmie Ng, Charles S. Fuchs, David Dornan. Inhibition of TBK1/IKBKE impacts tumor growth of KRAS-mutant colorectal cancers [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 5161. doi:10.1158/1538-7445.AM2017-5161