Abstract
In non-clinical studies, the proteasome inhibitor ixazomib inhibits cell growth in a broad panel of solid tumor cell lines in vitro. In contrast, antitumor activity in xenograft tumors is model-dependent, with some solid tumors showing no response to ixazomib. In this study we examined factors responsible for ixazomib sensitivity or resistance using mouse xenograft models. A survey of 14 non-small cell lung cancer (NSCLC) and 6 colon xenografts showed a striking relationship between ixazomib activity and KRAS genotype; tumors with wild-type (WT) KRAS were more sensitive to ixazomib than tumors harboring KRAS activating mutations. To confirm the association between KRAS genotype and ixazomib sensitivity, we used SW48 isogenic colon cancer cell lines. Either KRAS-G13D or KRAS-G12V mutations were introduced into KRAS-WT SW48 cells to generate cells that stably express activated KRAS. SW48 KRAS WT tumors, but neither SW48-KRAS-G13D tumors nor SW48-KRAS-G12V tumors, were sensitive to ixazomib in vivo. Since activated KRAS is known to be associated with metabolic reprogramming, we compared metabolite profiling of SW48-WT and SW48-KRAS-G13D tumors treated with or without ixazomib. Prior to treatment there were significant metabolic differences between SW48 WT and SW48-KRAS-G13D tumors, reflecting higher oxidative stress and glucose utilization in the KRAS-G13D tumors. Ixazomib treatment resulted in significant metabolic regulation, and some of these changes were specific to KRAS WT tumors. Depletion of free amino acid pools and activation of GCN2-eIF2α-pathways were observed both in tumor types. However, changes in lipid beta oxidation were observed in only the KRAS WT tumors. The non-clinical data presented here show a correlation between KRAS genotype and ixazomib sensitivity in NSCLC and colon xenografts and provide new evidence of regulation of key metabolic pathways by proteasome inhibition.
Highlights
The ubiquitin proteasome system processes the majority of cellular proteins, including proteins involved in growth, cell cycle regulation and apoptosis [1,2,3]
In this study we report a striking correlation between KRAS genotype and ixazomib sensitivity in a panel of non small cell lung cancer (NSCLC) and colon xenograft models
(C) in various non-small cell lung cancer (NSCLC) and colon xenografts at different time points following a single IV administration of maximum tolerated dose (MTD) dose of ixazomib. % 20S β5-inhibition was calculated by considering the average (n = 3 for treatment group or 4 for vehicle group) tumor 20S activity of vehicle treated animals as 100%
Summary
The ubiquitin proteasome system processes the majority of cellular proteins, including proteins involved in growth, cell cycle regulation and apoptosis [1,2,3]. PIs have demonstrated a wide range of effects on MM cells and their bone marrow microenvironment. This includes effects on cell cycle, NF-kB inhibition, and apoptotic regulators as well as induction of the integrated stress response, inhibition of IL-6 production and signaling, and many others [7,8]. All 3 cell lines were sensitive to ixazomib in the in vitro cell viability assay (Fig 2A). There was a clear difference in the in vivo sensitivity to ixazomib in SW48, SW48-G13D and SW48-G12V xenograft tumors. SW48 xenografts with wild-type KRAS responded to ixazomib treatment with T/C of 0.42 (Fig 2B). Neither the SW48-G13D nor SW48-G12V xenograft model was sensitive to ixazomib
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
