Back to Search
Start Over
Abstract 1027: Inhibiting pathways predicted from a steroid hormone gene signature yields synergistic antitumor effects in lung cancer
- Source :
- Cancer Research. 79:1027-1027
- Publication Year :
- 2019
- Publisher :
- American Association for Cancer Research (AACR), 2019.
-
Abstract
- Mounting preclinical and clinical evidence suggest an involvement of estrogen signaling in promoting non-small cell lung cancer (NSCLC) progression. In estrogen receptor β-positive (ERβ) cases, we previously found seven genes within the prediction analysis of microarrays 50 gene (PAM50) panel that showed strong association in predicting prognosis of NSCLC patients, with Myc, MIA, FGFR4, CXXC5, Grb-7 and FOXC1 being upregulated while PR was downregulated in highly aggressive lung tumors. These genes described one network containing ERβ and human epidermal growth factor receptor 2/3 (HER2/HER3) signaling, which suggests that these two interacting pathways define lung tumors with more aggressive biology. Here, we sought to evaluate the therapeutic potential of combining the pan-HER tyrosine kinase inhibitor, Dacomitinib, and the ER antagonist, Fulvestrant in NSCLC. Cell viability assay in three different human NSCLC cell lines 201T (EGFR wild-type), A549 (K-ras mutant) and HCC827 (EGFR exon 19 deletion) showed strong synergy between Dacomitinib and Fulvestrant, as determined by a combination index < 1. The combination strongly inhibited p-EGFR, p-HER2, p-HER3, p-HER4, and the downstream signaling p-AKT and p-MAPK compared to single treatments. Mechanistically, the transcription activity of activator protein-1 (AP-1) family members Fos and Jun were significantly reduced, as detected by the ability of AP-1 to bind to DNA. Expression of c-Myc and CyclinD1 were also significantly inhibited by the combination. In NSCLC cell lines, the combination reversed the gene signature associated with poor prognosis with c-Myc, MIA, CXXC5, FGFR4, Grb-7, FOXC1 being downregulated while PR was upregulated. Similarly, the AP-1 inhibitor t-5224 mimicked the effects of the combination in reversing the PAM50 gene signature, suggesting that the combination’s effect is largely mediated by AP-1 downregulation. In vivo, the combination also revealed a synergistic effect, measured by the combination ratio method (> 1), and induced tumor regression in 201T and A549 xenografts, with average tumor volume significantly lower than the single treatment groups. The immunohistochemical analysis of the xenografts revealed significant downregulation in Ki67. Western blot analysis of the tumor lysates from the combination treatment groups showed an increase in cleaved caspase-3 and a decrease in both ER and HER signaling. The PAM50 gene signature was also reversed in both xenograft studies detected by real-time-qPCR. Similar effects were seen for c-Myc and PR at the protein levels detected by immunohistochemistry staining. These observations encouragingly support the use of this combination clinically in NSCLC, considering its ability to suppress tumor growth and produce a gene signature that predicts better clinical outcomes, as assessed by the PAM50 genes. Citation Format: Abdulaziz A. Almotlak, Mariya Farooqui, Jill M. Siegfried. Inhibiting pathways predicted from a steroid hormone gene signature yields synergistic antitumor effects in lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1027.
- Subjects :
- 0301 basic medicine
Cancer Research
Fulvestrant
medicine.drug_class
Estrogen receptor
Cancer
Fibroblast growth factor receptor 4
Gene signature
Biology
medicine.disease
Tyrosine-kinase inhibitor
Dacomitinib
03 medical and health sciences
chemistry.chemical_compound
030104 developmental biology
0302 clinical medicine
Oncology
chemistry
030220 oncology & carcinogenesis
medicine
Cancer research
Lung cancer
medicine.drug
Subjects
Details
- ISSN :
- 15387445 and 00085472
- Volume :
- 79
- Database :
- OpenAIRE
- Journal :
- Cancer Research
- Accession number :
- edsair.doi...........becddcd871a9992818f6e256fc935f38