Arendt, Kristina Anna Maria (2020): An in vivo inflammatory loop potentiates KRAS blockade. Dissertation, LMU München: Faculty of Medicine |
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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) |
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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 |
MD5 Checksum of the PDF-file: | 566c308b9bea91c7a9b278536863062e |
Signature of the printed copy: | 0700/UMD 19132 |
ID Code: | 26150 |
Deposited On: | 09. Jul 2020 14:41 |
Last Modified: | 23. Oct 2020 14:01 |