A High Immune-Related Index with the Suppression of CGAS-STING Pathway is a Key Determinant to Herceptin Resistance in HER2+ Breast Cancer

Overview

Journal Int J Biol Sci

Specialty Biology

Date 2024 Jul 12

PMID 38993569

Authors

Ruizhao Cai

Qingshan Chen

Dechang Zhao

Yan Wang

Ling Zhou

Kaiming Zhang

Jialu Shan

Zhiling Li

Yuhong Chen

Hailiang Zhang

Gongkan Feng

Xiaofeng Zhu

Rong Deng

Jun Tang

Affiliations

Soon will be listed here.

Abstract

Resistance to HER2-targeted therapy is the major cause of treatment failure in patients with HER2+ breast cancer (BC). Given the key role of immune microenvironment in tumor development, there is a lack of an ideal prognostic model that fully accounts for immune infiltration. In this study, WGCNA analysis was performed to discover the relationship between immune-related signaling and prognosis of HER2+ BC. After Herceptin-resistant BC cell lines established, transcriptional profiles of resistant cell line and RNA-sequencing data from GSE76360 cohort were analyzed for candidate genes. 85 samples of HER2+ BC from TCGA database were analyzed by the Cox regression, XGBoost and Lasso algorithm to generalize a credible immune-related prognostic index (IRPI). Correlations between the IRPI signature and tumor microenvironment were further analyzed by multiple algorithms, including single-cell RNA sequencing data analysis. Patients with high IRPI had suppressive tumor immune microenvironment and worse prognosis. The suppression of type I interferon signaling indicated by the IRPI in Herceptin-resistant HER2+ BC was validated. And we elucidated that the suppression of cGAS-STING pathway is the key determinant underlying immune escape in Herceptin-resistant BC with high IRPI. A combination of STING agonist and DS-8201 could serve as a new strategy for Herceptin-resistant HER2+ BC.

References

Emens L, Esteva F, Beresford M, Saura C, De Laurentiis M, Kim S . Trastuzumab emtansine plus atezolizumab versus trastuzumab emtansine plus placebo in previously treated, HER2-positive advanced breast cancer (KATE2): a phase 2, multicentre, randomised, double-blind trial. Lancet Oncol. 2020; 21(10):1283-1295. DOI: 10.1016/S1470-2045(20)30465-4. View

Wang Y, Luo J, Alu A, Han X, Wei Y, Wei X . cGAS-STING pathway in cancer biotherapy. Mol Cancer. 2020; 19(1):136. PMC: 7472700. DOI: 10.1186/s12943-020-01247-w. View

Jiang M, Chen P, Wang L, Li W, Chen B, Liu Y . cGAS-STING, an important pathway in cancer immunotherapy. J Hematol Oncol. 2020; 13(1):81. PMC: 7310007. DOI: 10.1186/s13045-020-00916-z. View

Musolino A, Boggiani D, Sikokis A, Rimanti A, Pellegrino B, Vattiato R . Prognostic risk factors for treatment decision in pT1a,b N0M0 HER2-positive breast cancers. Cancer Treat Rev. 2016; 43:1-7. DOI: 10.1016/j.ctrv.2015.11.010. View

Denkert C, von Minckwitz G, Darb-Esfahani S, Lederer B, Heppner B, Weber K . Tumour-infiltrating lymphocytes and prognosis in different subtypes of breast cancer: a pooled analysis of 3771 patients treated with neoadjuvant therapy. Lancet Oncol. 2017; 19(1):40-50. DOI: 10.1016/S1470-2045(17)30904-X. View

Yu J, Yang K, Zheng J, Zhao W, Sun X . Synergistic tumor inhibition of colon cancer cells by nitazoxanide and obeticholic acid, a farnesoid X receptor ligand. Cancer Gene Ther. 2020; 28(6):590-601. PMC: 8203497. DOI: 10.1038/s41417-020-00239-8. View

Zhou Y, Tang X, Niu L, Liu Y, Wang B, He J . Ectodermal-neural cortex 1 as a novel biomarker predicts poor prognosis and induces metastasis in breast cancer by promoting Wnt/β-catenin pathway. J Cell Mol Med. 2020; 24(15):8826-8835. PMC: 7412682. DOI: 10.1111/jcmm.15520. View

Dai J, Huang Y, He X, Zhao M, Wang X, Liu Z . Acetylation Blocks cGAS Activity and Inhibits Self-DNA-Induced Autoimmunity. Cell. 2019; 176(6):1447-1460.e14. PMC: 8274936. DOI: 10.1016/j.cell.2019.01.016. View

Li Y, Tsang J, Tam F, Loong T, Tse G . Comprehensive characterization of HER2-low breast cancers: implications in prognosis and treatment. EBioMedicine. 2023; 91:104571. PMC: 10130469. DOI: 10.1016/j.ebiom.2023.104571. View

10.

Gan Y, Li X, Han S, Liang Q, Ma X, Rong P . The cGAS/STING Pathway: A Novel Target for Cancer Therapy. Front Immunol. 2022; 12:795401. PMC: 8761794. DOI: 10.3389/fimmu.2021.795401. View

11.

Xia T, Konno H, Ahn J, Barber G . Deregulation of STING Signaling in Colorectal Carcinoma Constrains DNA Damage Responses and Correlates With Tumorigenesis. Cell Rep. 2016; 14(2):282-97. PMC: 4845097. DOI: 10.1016/j.celrep.2015.12.029. View

12.

Su S, Song E . The systemic effect of type 1 interferon responsiveness on tumor immunotherapy. Nat Immunol. 2022; 23(8):1141-1143. DOI: 10.1038/s41590-022-01275-2. View

13.

Sceneay J, Goreczny G, Wilson K, Morrow S, DeCristo M, Ubellacker J . Interferon Signaling Is Diminished with Age and Is Associated with Immune Checkpoint Blockade Efficacy in Triple-Negative Breast Cancer. Cancer Discov. 2019; 9(9):1208-1227. PMC: 11167954. DOI: 10.1158/2159-8290.CD-18-1454. View

14.

McNamara K, Caswell-Jin J, Joshi R, Ma Z, Kotler E, Bean G . Spatial proteomic characterization of HER2-positive breast tumors through neoadjuvant therapy predicts response. Nat Cancer. 2021; 2(4):400-413. PMC: 8713949. DOI: 10.1038/s43018-021-00190-z. View

15.

Loi S, Giobbie-Hurder A, Gombos A, Bachelot T, Hui R, Curigliano G . Pembrolizumab plus trastuzumab in trastuzumab-resistant, advanced, HER2-positive breast cancer (PANACEA): a single-arm, multicentre, phase 1b-2 trial. Lancet Oncol. 2019; 20(3):371-382. DOI: 10.1016/S1470-2045(18)30812-X. View

16.

de Queiroz N, Xia T, Konno H, Barber G . Ovarian Cancer Cells Commonly Exhibit Defective STING Signaling Which Affects Sensitivity to Viral Oncolysis. Mol Cancer Res. 2018; 17(4):974-986. PMC: 6445711. DOI: 10.1158/1541-7786.MCR-18-0504. View

17.

Meric-Bernstam F, Sweis R, Kasper S, Hamid O, Bhatia S, Dummer R . Combination of the STING Agonist MIW815 (ADU-S100) and PD-1 Inhibitor Spartalizumab in Advanced/Metastatic Solid Tumors or Lymphomas: An Open-Label, Multicenter, Phase Ib Study. Clin Cancer Res. 2022; 29(1):110-121. PMC: 11188043. DOI: 10.1158/1078-0432.CCR-22-2235. View

18.

Boukhaled G, Gadalla R, Elsaesser H, Abd-Rabbo D, Quevedo R, Yang S . Pre-encoded responsiveness to type I interferon in the peripheral immune system defines outcome of PD1 blockade therapy. Nat Immunol. 2022; 23(8):1273-1283. DOI: 10.1038/s41590-022-01262-7. View

19.

Hurvitz S, Hegg R, Chung W, Im S, Jacot W, Ganju V . Trastuzumab deruxtecan versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer: updated results from DESTINY-Breast03, a randomised, open-label, phase 3 trial. Lancet. 2022; 401(10371):105-117. DOI: 10.1016/S0140-6736(22)02420-5. View

20.

Borden E . Interferons α and β in cancer: therapeutic opportunities from new insights. Nat Rev Drug Discov. 2019; 18(3):219-234. DOI: 10.1038/s41573-018-0011-2. View