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Arendt, K.A.M. ; Ntaliarda, G.* ; Armenis, V.* ; Kati, D.* ; Henning, C. ; Giotopoulou, G.A. ; Pepe, M. ; Klotz, L.V. ; Lamort, A.-S. ; Hatz, R.A.* ; Kobold, S.* ; Schamberger, A.C. ; Stathopoulos, G.T.

An in vivo inflammatory loop potentiates KRAS blockade.

Biomedicines 10:592 (2022)
Publ. Version/Full Text Research data DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
KRAS (KRAS proto-oncogene, GTPase) inhibitors perform less well than other targeted drugs in vitro and fail clinical trials. To investigate a possible reason for this, we treated human and murine tumor cells with KRAS inhibitors deltarasin (targeting phosphodiesterase-δ), cysmethynil (targeting isoprenylcysteine carboxylmethyltransferase), and AA12 (targeting KRASG12C ), and silenced/overexpressed mutant KRAS using custom-designed vectors. We showed 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 (CCL2)/interleukin-1 beta (IL-1β)-mediated signaling loop for sustained tumorigenicity. Indeed, KRAS-mutant tumors did not respond to deltarasin in C-C motif chemokine receptor 2 (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 poor predicted survival. Our findings support that in vitro cellular systems are suboptimal for anti-KRAS drug screens, as these drugs function to suppress interleukin-1 receptor 1 (IL1R1) expression and myeloid IL-1β-delivered pro-growth effects in vivo. Moreover, the findings support that IL-1β blockade might be suitable for therapy for KRAS-mutant cancers.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Deltarasin ; Il-1β ; Il1r1 ; Inflammation ; Kras ; Kras Mutation ; Kras G12c ; Lung Cancer
ISSN (print) / ISBN 2227-9059
e-ISSN 2227-9059
Journal Biomedicines
Quellenangaben Volume: 10, Issue: 3, Pages: , Article Number: 592 Supplement: ,
Publisher MDPI
Publishing Place Basel, Switzerland
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Lung Health and Immunity (LHI)
Grants European Respiratory Society