title: 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.
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.
authors.affiliation: Takeda Pharmaceuticals International Co., Cambridge, Massachusetts, United States of America.
authors.forename: Nibedita
authors.initials: N
authors.lastname: Chattopadhyay
authors.affiliation: Takeda Pharmaceuticals International Co., Cambridge, Massachusetts, United States of America.
authors.forename: Allison J
authors.initials: AJ
authors.lastname: Berger
authors.affiliation: Takeda Pharmaceuticals International Co., Cambridge, Massachusetts, United States of America.
authors.forename: Erik
authors.initials: E
authors.lastname: Koenig
authors.affiliation: Takeda Pharmaceuticals International Co., Cambridge, Massachusetts, United States of America.
authors.forename: Bret
authors.initials: B
authors.lastname: Bannerman
authors.affiliation: Takeda Pharmaceuticals International Co., Cambridge, Massachusetts, United States of America.
authors.forename: James
authors.initials: J
authors.lastname: Garnsey
authors.affiliation: Takeda Pharmaceuticals International Co., Cambridge, Massachusetts, United States of America.
authors.forename: Hugues
authors.initials: H
authors.lastname: Bernard
authors.affiliation: Takeda Pharmaceuticals International Co., Cambridge, Massachusetts, United States of America.
authors.forename: Paul
authors.initials: P
authors.lastname: Hales
authors.affiliation: Takeda Pharmaceuticals International Co., Cambridge, Massachusetts, United States of America.
authors.forename: Angel
authors.initials: A
authors.lastname: Maldonado Lopez
authors.affiliation: Takeda Pharmaceuticals International Co., Cambridge, Massachusetts, United States of America.
authors.forename: Yu
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Takeda Pharmaceuticals International Co., Cambridge, Massachusetts, United States of America.
authors.forename: Jill
authors.initials: J
authors.lastname: Donelan
authors.affiliation: Takeda Pharmaceuticals International Co., Cambridge, Massachusetts, United States of America.
authors.forename: Kristen
authors.initials: K
authors.lastname: Jordan
authors.affiliation: Takeda Pharmaceuticals International Co., Cambridge, Massachusetts, United States of America.
authors.forename: Stephen
authors.initials: S
authors.lastname: Tirrell
authors.affiliation: Takeda Pharmaceuticals International Co., Cambridge, Massachusetts, United States of America.
authors.forename: Bradley
authors.initials: B
authors.lastname: Stringer
authors.affiliation: Takeda Pharmaceuticals International Co., Cambridge, Massachusetts, United States of America.
authors.forename: Cindy
authors.initials: C
authors.lastname: Xia
authors.affiliation: Takeda Pharmaceuticals International Co., Cambridge, Massachusetts, United States of America.
authors.forename: Greg
authors.initials: G
authors.lastname: Hather
authors.affiliation: Takeda Pharmaceuticals International Co., Cambridge, Massachusetts, United States of America.
authors.forename: Katherine
authors.initials: K
authors.lastname: Galvin
authors.affiliation: Takeda Pharmaceuticals International Co., Cambridge, Massachusetts, United States of America.
authors.forename: Mark
authors.initials: M
authors.lastname: Manfredi
authors.affiliation: Metabolon Inc, Durham, North Carolina, United States of America.
authors.forename: Nelson
authors.initials: N
authors.lastname: Rhodes
authors.affiliation: Takeda Pharmaceuticals International Co., Cambridge, Massachusetts, United States of America.
authors.forename: Ben
authors.initials: B
authors.lastname: Amidon
mesh_terms: D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001896:Boron Compounds / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005227:Fatty Acids / Q000378:metabolism; D051275:Glucose Transporter Type 4 / Q000096:biosynthesis; D005998:Glycine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D045325:HCT116 Cells; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D055442:Metabolome / Q000502:physiology; D051379:Mice; D010084:Oxidation-Reduction / Q000187:drug effects; D061988:Proteasome Inhibitors / Q000627:therapeutic use*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000596:Amino Acids; D000970:Antineoplastic Agents; D001896:Boron Compounds; D005227:Fatty Acids; D051275:Glucose Transporter Type 4; C117307:KRAS protein, human; D061988:Proteasome Inhibitors; C495692:SLC2A4 protein, human; C548400:ixazomib; D016283:Proto-Oncogene Proteins p21(ras); D005998:Glycine