An In Vivo Inflammatory Loop Potentiates KRAS Blockade

Arendt, Kristina A. M.; Ntaliarda, Giannoula; Armenis, Vasileios; Kati, Danai; Henning, Christin; Giotopoulou, Georgia A.; Pepe, Mario A. A.; Klotz, Laura V.; Lamort, Anne-Sophie; Hatz, Rudolf A.; Kobold, Sebastian; Schamberger, Andrea C.; Stathopoulos, Georgios T.

doi:10.3390/biomedicines10030592

Open AccessArticle

An In Vivo Inflammatory Loop Potentiates KRAS Blockade

by

Kristina A. M. Arendt

^1,2,†,

Giannoula Ntaliarda

^3,†

,

Vasileios Armenis

³,

Danai Kati

³,

Christin Henning

^1,2,

Georgia A. Giotopoulou

^1,2,3,

Mario A. A. Pepe

^1,2,

Laura V. Klotz

^1,2,

Anne-Sophie Lamort

^1,2

,

Rudolf A. Hatz

^2,4,5,

Sebastian Kobold

^2,6

,

Andrea C. Schamberger

^1,2,*,‡ and

Georgios T. Stathopoulos

^1,2,3,*,‡

¹

Comprehensive Pneumology Center (CPC), Institute of Lung Health and Immunity (LHI), Helmholtz Zentrum München, 81377 Munich, Germany

²

Member of the German Center for Lung Research (DZL), 35392 Gießen, Germany

³

Laboratory for Molecular Respiratory Carcinogenesis, Department of Physiology, Faculty of Medicine, University of Patras, 26504 Rio, Greece

⁴

Center for Thoracic Surgery, University Hospital, Ludwig-Maximilians-Universität (LMU), 81377 Munich, Germany

⁵

Asklepios Medical Center, 82131 Gauting, Germany

⁶

Center of Integrated Protein Science Munich (CIPS-M), Division of Clinical Pharmacology, Department of Medicine IV, Klinikum der Universität München, Lindwurmstraße 2a, 80337 Munich, Germany

^*

Authors to whom correspondence should be addressed.

^†

These authors contributed equally to this work.

^‡

These authors contributed equally to this work.

Biomedicines 2022, 10(3), 592; https://doi.org/10.3390/biomedicines10030592

Submission received: 28 January 2022 / Revised: 24 February 2022 / Accepted: 25 February 2022 / Published: 3 March 2022

(This article belongs to the Special Issue Resistance to Targeted Therapies in Human Cancer)

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Abstract

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 KRAS^G12C), 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.

Keywords: deltarasin; IL-1β; IL1R1; KRAS; KRAS mutation; KRAS^G12C; inflammation; lung cancer

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MDPI and ACS Style

Arendt, K.A.M.; Ntaliarda, G.; Armenis, V.; Kati, D.; Henning, C.; Giotopoulou, G.A.; Pepe, M.A.A.; Klotz, L.V.; Lamort, A.-S.; Hatz, R.A.; et al. An In Vivo Inflammatory Loop Potentiates KRAS Blockade. Biomedicines 2022, 10, 592. https://doi.org/10.3390/biomedicines10030592

AMA Style

Arendt KAM, Ntaliarda G, Armenis V, Kati D, Henning C, Giotopoulou GA, Pepe MAA, Klotz LV, Lamort A-S, Hatz RA, et al. An In Vivo Inflammatory Loop Potentiates KRAS Blockade. Biomedicines. 2022; 10(3):592. https://doi.org/10.3390/biomedicines10030592

Chicago/Turabian Style

Arendt, Kristina A. M., Giannoula Ntaliarda, Vasileios Armenis, Danai Kati, Christin Henning, Georgia A. Giotopoulou, Mario A. A. Pepe, Laura V. Klotz, Anne-Sophie Lamort, Rudolf A. Hatz, and et al. 2022. "An In Vivo Inflammatory Loop Potentiates KRAS Blockade" Biomedicines 10, no. 3: 592. https://doi.org/10.3390/biomedicines10030592

APA Style

Arendt, K. A. M., Ntaliarda, G., Armenis, V., Kati, D., Henning, C., Giotopoulou, G. A., Pepe, M. A. A., Klotz, L. V., Lamort, A.-S., Hatz, R. A., Kobold, S., Schamberger, A. C., & Stathopoulos, G. T. (2022). An In Vivo Inflammatory Loop Potentiates KRAS Blockade. Biomedicines, 10(3), 592. https://doi.org/10.3390/biomedicines10030592

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An In Vivo Inflammatory Loop Potentiates KRAS Blockade

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