Abstract 424: Chromosomal instability leads to EGFR-TKI refractoriness via cGAS-STING activation in EGFR-mutated non-small cell lung cancer
Authors: Kimio Yonesaka, Takashi Kurosaki, Junko Tanizaki, Hisato Kawakami, Kaoru Tanaka, Osamu Maenishi, Shiki Takamura, Kazuko Sakai, Yasutaka Chiba, Takeshi Teramura, Hiroki Goto, Eri Otsuka, Hiroaki Okida, Masanori Funabashi, Yuuri Hashimoto, Kenji Hirotani, Yasuki Kamai, Takashi Kagari, Kazuto Nishio, Kazuhiro Kakimi, Hidetoshi Hayashi
Journal: Cancer Research (2025)

Abstract Background: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are a standard therapy for EGFR-mutated non-small cell lung cancer (NSCLC); however, their efficacy is inconsistent. Tumor inflammation is observed in subpopulations of EGFR-mutated NSCLC tumors, which potentially influence the efficacy of anti-cancer agents. Chromosomal instability (CIN) is a trigger of tumor inflammation in malignancies. CIN causes accumulation of cytoplasmic DNA, which subsequently activates cGAS-STING signaling, resulting in tumor inflammation. However, it is unclear whether CIN affects susceptibility to EGFR-TKIs. Materials and methods: The current study was based on the genomic and transcriptomic analyses of 67 tissue samples obtained from patients with EGFR-mutated NSCLC before EGFR-TKI treatment (n = 32) and after the acquisition of EGFR-TKI resistance (n = 35). RNA-Seq data were analyzed using the CIBERSORTx, GenePattern for ssGSEA, Carcinoma EcoTyper, and Tumor Immune Dysfunction and Exclusion (TIDE). The CIN score was calculated as previously reported (S. L. Carter et al. Nat. Genet. 2006), using the mean of the normalized gene expression data for the 70 genes comprising the signature. Results: CIN is associated with poor outcomes of EGFR-TKI treatment in patients with EGFR-mutated NSCLC (CIN-low group vs CIN-high group; median PFS 16.7 vs. 11.0 months, HR 3.274, p = 0.005). Transcriptomic analysis revealed that cGAS-STING signaling is enhanced and the innate immune response is prominent in chromosomally unstable cancers. Consistently, EGFR-mutated H1975dnMCAK cells, which frequently underwent chromosomal mis-segregation, demonstrated a refractoriness to EGFR-TKI osimertinib compared to control cells in vitro growth inhibition assay (IC50 values; 6 vs 0.005 μM, respectively). H1975dnMCAK cells showed an activated signaling of cGAS-STING and an increase of its downstream IL-6. Several protumor signaling, including IL-6 and NF-κB, was activated in chromosomally unstable EGFR-mutated NSCLC tumor. Finally, chromosomally unstable H1975dnMCAK cells showed enhanced epithelial-mesenchymal transition (EMT) and blockade of cGAS-STING-TBK1 signaling reversed EMT, and consequently restored susceptibility to EGFR-TKIs both in vitro and in vivo. Conclusion: These results suggest that CIN may induce EGFR-TKI refractoriness via cGAS-STING activation in EGFR-mutated NSCLC. Furthermore, cGAS-STING-TBK1 inhibitors, in combination with EGFR-TKIs, represent a rational therapeutic strategy that should be evaluated in patients with CIN-induced EGFR-TKI resistant NSCLC. Citation Format: Kimio Yonesaka, Takashi Kurosaki, Junko Tanizaki, Hisato Kawakami, Kaoru Tanaka, Osamu Maenishi, Shiki Takamura, Kazuko Sakai, Yasutaka Chiba, Takeshi Teramura, Hiroki Goto, Eri Otsuka, Hiroaki Okida, Masanori Funabashi, Yuuri Hashimoto, Kenji Hirotani, Yasuki Kamai, Takashi Kagari, Kazuto Nishio, Kazuhiro Kakimi, Hidetoshi Hayashi. Chromosomal instability leads to EGFR-TKI refractoriness via cGAS-STING activation in EGFR-mutated non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 424.