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Deng, B. ; Trassl, L. ; Jia, J. ; Skiadas, G.* ; Ntaliarda, G.* ; Behrend, S.J. ; Schamberger, A.C. ; Yildirim, A.Ö. ; Stathopoulos, G.T. ; Asarian, L. ; Chateau, M.d.* ; Fernandez, I.E.*

Targeting KRAS-mutant Lung Adenocarcinoma Tumors Through IL-1ß Inhibition.

Am. J. Respir. Crit. Care Med. 211, A3105 - A3105 (2025)
DOI
Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
RATIONALE Lung adenocarcinoma (LUAD) frequently harbors KRAS mutations and is highly aggressive and resistant to conventional therapies. KRAS mutations drive tumorigenesis by altering pathways like NF-κB, suggesting that CCL2, VCAN and IL-1ß signaling within the tumor microenvironment is important to LUAD's etiology. Using Isunakinra, a potent IL-1 receptor antagonist, we tested whether these signaling pathways and immune cell recruitment contribute to suppressing the pro-tumorigenic environment fostered by KRAS mutations. METHODS and RESULTS Here we developed a bioluminescence-based reporting system (NF-κB.GFP.Luc; pNGL) to monitor NF-κB activity in four KRAS-mutant lines (KM: LLC, MC38, AE17, FULA1) and two KRAS wild-type lines (KW: B16F10, PANO2). When treated with Isunakinra, NF-κB activity was significantly inhibited in KM vs KW cell lines (p<0.001). FVB mice were injected subcutaneously with KM or KW and treated with Isunakinra (n= 5-6/cell line) for 7 days Tumor growth, pulmonary metastasis and malignant pulmonary effusion were all significantly decreased by Isunakinra (KM vs KW, p<0.001). Next, mice were treated with urethane (1g/kg/mouse, n=10/group), a reliable system for generating KRAS-mutant tumors. Isunakinra (20mg/kg; twice-weekly) was administered for 30 days either early during the first month post-induction or later during the fifth month post-induction. Tumor number and burden were assessed, and KRAS mutations (Q61 and G12/G13) were identified using ddPCR. Immunofluorescent labeling of lung sections was used to assess the presence of macrophages and CCL2/VCAN protein expression. Early treatment reduced both tumor number and burden by approximately 25% (vs non-treated, p < 0.05), while late treatment achieved a 40% reduction (p < 0.05), with no differences between early and late timing. KRAS mutations were confirmed in our model, and subtypes remained unchanged across groups (p > 0.05). CD68+ macrophages increased within the tumor area during late treatment (p= 0.053), while peritumor CD68+ macrophages decreased significantly (p < 0.05). CCR2 expression in tumor regions was reduced by 40% in the late-treated group (vs non-treated, p = 0.051). Interestingly, late-treated mice increased CCL2 expression, correlating with reduced tumor number and burden in early-treated mice (p<0.05) and suggesting compensatory changes in chemokine-receptor dynamics. VCAN levels were not significantly altered. CONCLUSIONS Overall, our data suggest that Isunakinra effectively influences the KRAS tumorgenicity via CCL2 signaling loop, reducing tumor growth by modulating the immune microenvironment. These results support its further investigation as a modulator of immune signaling and immune cell recruitment, and as a therapeutic approach for KRAS-mutated LUAD.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Meeting abstract
Korrespondenzautor
ISSN (print) / ISBN 1073-449X
e-ISSN 1535-4970
Zeitschrift American Journal of Respiratory and Critical Care Medicine
Quellenangaben Band: 211, Heft: Abstracts, Seiten: A3105 - A3105 Artikelnummer: , Supplement: ,
Verlag American Thoracic Society
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Lung Health and Immunity (LHI)