An in vivo inflammatory loop potentiates KRAS blockade

Arendt, Kristina Anna Maria (2020): An in vivo inflammatory loop potentiates KRAS blockade. Dissertation, LMU München: Faculty of Medicine

Abstract

KRAS inhibitors perform inferior to other targeted drugs. To investigate a possible reason for this, we treated cancer cells with KRAS inhibitors deltarasin (targeting phosphodiesterase-δ), cysmethynil (targeting isoprenylcysteine carboxylmethyltransferase), and AA12 (targeting KRASG12C), and silenced/overexpressed mutant KRAS using custom vectors. We show that KRAS-mutant tumor cells exclusively respond to KRAS blockade in vivo, because the oncogene co-opts host myeloid cells via a C-C-motif chemokine ligand 2/interleukin-1β-mediated signaling loop for sustained tumorigenicity. Indeed, KRAS-mutant tumors did not respond to deltarasin in Ccr2 and Il1b gene-deficient mice, but were deltarasin-sensitive in wild-type and Ccr2-deficient mice adoptively transplanted with wild-type murine bone marrow. A KRAS-dependent pro-inflammatory transcriptome was prominent in human cancers with high KRAS mutation prevalence and predicted poor survival. Hence the findings support that in vitro systems are suboptimal for anti-KRAS drug screens, and suggest that interleukin-1β blockade might be specific for KRAS-mutant cancers.

• Item Type: Theses (Dissertation, LMU Munich)
• Keywords: KRAS, inflammation, lung cancer, targeted therapy
• Subjects: 600 Technology, Medicine; 600 Technology, Medicine > 610 Medical sciences and medicine
• Faculties: Faculty of Medicine
• Language: English
• Date of oral examination: 19. May 2020
• 1. Referee: Hatz, Rudolf
• Signature of the printed copy: 0700/UMD 19132