Regulation of tumor metabolism by the investigational proteasome inhibitor ixazomib in KRAS wild-type and KRAS mutant xenograft tumors.

The investigational proteasome inhibitor ixazomib (MLN2238) inhibits cell growth in a broad panel of solid tumor and hematological cell lines when tested in vitro. In contrast, antitumor activity in xenograft-bearing mice is model-dependent, with some solid tumor models showing no response to ixazomib treatment. A survey of 15 NSCLC and 6 colon xenograft models showed a striking relationship between the degree of antitumor activity of ixazomib and KRAS genotype. Tumors with wild-type (WT) KRAS showed higher sensitivity to ixazomib compared to the tumors harboring a KRAS activating mutation. These xenografts included cell-line-derived subcutaneous xenografts as well as patient derived primary tumors. To confirm that KRAS mutation impacts response to ixazomib, we used SW48 isogenic colon cancer cell lines, in which a KRAS-G13D mutation was introduced into KRAS-WT SW48 cells to generate stable SW48-KRAS-G13D cells. Although in vitro sensitivity to ixazomib was similar between the paired cell lines, in vivo antitumor activity was observed in only SW48 KRAS WT tumors, but not SW48-KRAS-G13D tumors. These data confirm the association of KRAS status and response to ixazomib. Since KRAS activating mutations are known to be associated with metabolic reprogramming, we performed metabolite profiling using in vivo SW48 isogenic tumor pairs treated with or without ixazomib. As expected, prior to treatment there were significant baseline differences between SW48 WT and SW48-KRAS-G13D tumor metabolite profiles in categories such as glutathione levels and glycogen breakdown intermediates, reflecting higher oxidative stress and glucose utilization in the KRAS-G13D tumors. After a single dose of ixazomib, significant metabolic regulation was noted in categories including free amino acid pools, and polyamine levels, and some of these changes were more pronounced in the SW48 KRAS WT tumors as compared to the KRAS-G13D tumors. Our data also showed activation of GCN2 mediated signaling following ixazomib treatment, possibly as a result of amino acid deprivation in the tumors. The results suggest additional non-clinical avenues to explore mechanisms of sensitivity and resistance to proteasome inhibitors in solid tumors. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B156. Citation Format: Nibedita Chattopadhyay, Allison Berger, James Garnsey, Hugues Bernard, Erik Koenig, Eric Lightcap, Ben Amidon. Regulation of tumor metabolism by the investigational proteasome inhibitor ixazomib in KRAS wild-type and KRAS mutant xenograft tumors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B156.