Journal Article

KRAS Genotype Correlates with Proteasome Inhibitor Ixazomib Activity in Preclinical In Vivo Models of Colon and Non-Small Cell Lung Cancer: Potential Role of Tumor Metabolism

Berger, Allison J., Bernard, Hugues, Manfredi, Mark, Koenig, Erik, Donelan, Jill, Bannerman, Bret, Galvin, Katherine, Tirrell, Stephen, Xia, Cindy, Yang, Yu, Amidon, Ben, Hather, Greg, Chattopadhyay, Nibedita, Maldonado Lopez, Angel, Jordan, Kristen, Rhodes, Nelson, Hales, Paul, Stringer, Bradley, Garnsey, James

2015

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Amino acids / Amino Acids - metabolism / Animal models / Animals / Anticancer properties / Antineoplastic Agents - therapeutic use / Antitumor activity / Biotechnology / Boron Compounds - therapeutic use / Cancer / Cancer therapies / Carcinoma, Non-Small-Cell Lung - drug therapy / Carcinoma, Non-Small-Cell Lung - metabolism / Cell cycle / Cell Line, Tumor / Cell Proliferation - drug effects / Clinical trials / Colon / Colon cancer / Colonic Neoplasms - drug therapy / Colonic Neoplasms - metabolism / Colorectal cancer / Dosage and administration / Drug Resistance, Neoplasm - genetics / Drug therapy / Fatty acids / Fatty Acids - metabolism / Gene expression / Genetic aspects / Genotypes / Glucose metabolism / Glucose Transporter Type 4 - biosynthesis / Glycine - analogs & derivatives / Glycine - therapeutic use / HCT116 Cells / Health aspects / Humans / Immunoglobulins / Inhibitors / Ixazomib / K-Ras protein / Kinases / Laboratory animals / Lung cancer / Lung diseases / Lung Neoplasms - drug therapy / Lung Neoplasms - metabolism / Metabolic pathways / Metabolism / Metabolites / Metabolome - physiology / Metastasis / Mice / Multiple myeloma / Mutation / Non-small cell lung cancer / Non-small cell lung carcinoma / Oxidation / Oxidation-Reduction - drug effects / Oxidative stress / Patient outcomes / Pharmaceuticals / Proteasome Inhibitors - therapeutic use / Proteasomes / Proteins / Proto-Oncogene Proteins p21(ras) - genetics / Sensitivity / Solid tumors / Tumor cell lines / Tumors / Xenograft Model Antitumor Assays / Xenografts / Yang, Cindy