nach oben

Journal of Cancer Research and Clinical Oncology

Erschienen in:

31.08.2023 | Research

Osimertinib resistance prognostic gene signature: STRIP2 is associated with immune infiltration and tumor progression in lung adenocarcinoma

verfasst von: Guixing Zhang, Huiting Guan, Yi-Le Ning, Kainan Yao, Hao Tang, Gulizeba Muhetaer, Hang Li, Jihong Zhou

Erschienen in: Journal of Cancer Research and Clinical Oncology | Ausgabe 17/2023

Einloggen, um Zugang zu erhalten

Abstract

Objective

Although the use of osimertinib can significantly improve the survival time of lung adenocarcinoma (LUAD) patients with epithelial growth factor receptor mutation, eventually drug resistance will limit the survival benefit of most patients. This study aimed to develop a novel prognostic predictive signature based on genes associated with osimertinib resistance.

Methods

The differentially expressed genes (DEGs) associated with osimertinib resistance in LUAD were screened from Gene Expression Omnibus datasets and The Cancer Genome Atlas datasets. Multivariate cox regression was used to establish a prognostic signature, and then a nomogram was developed to predict the survival probability of LUAD patients. We used ROC curve and DCA curve to evaluate its clinical prediction accuracy and net benefit. In addition, the differentially expressed genes significantly associated with prognosis were selected for immune infiltration analysis and drug sensitivity analysis, and their roles in the progression of lung adenocarcinoma were verified by in vitro experiments.

Results

Our evaluation results indicated that the new nomogram had higher clinical prediction accuracy and net benefit value than the TN nomogram. Further analysis showed that patients with low STRIP2 expression had a higher level of immune response, and may be more likely to benefit from immune checkpoint inhibitors and conventional antitumor drugs. This may help to select more precise and appropriate therapy for LUAD patients with osimertinib resistance. Furthermore, in vitro experiments showed that STRIP2 promoted the LUAD cells proliferation, migration and invasion. This further demonstrates the importance of this gene signature for prognostic prediction.

Conclusion

We developed a reliable prognostic model based on DEGs associated with osimertinib resistance and screened for biomarker that can predict the immune response in LUAD patients, which may help in the selection of treatment regimens after osimertinib resistance.

Graphical Abstract

Nur mit Berechtigung zugänglich

An L, Cao Z, Nie P, Zhang H, Tong Z, Chen F, Tang Y, Han Y, Wang W, Zhao Z, Zhao Q, Yang Y, Xu Y, Fang G, Shi L, Xu H, Ma H, Jiao S, Zhou Z (2022) Combinatorial targeting of Hippo-STRIPAK and PARP elicits synthetic lethality in gastrointestinal cancers. J Clin Invest 132(9):e155468PubMedPubMedCentral

Aras S, Zaidi MR (2017) TAMeless traitors: macrophages in cancer progression and metastasis. Br J Cancer 117(11):1583–1591PubMedPubMedCentral

Bai SW, Herrera-Abreu MT, Rohn JL, Racine V, Tajadura V, Suryavanshi N, Bechtel S, Wiemann S, Baum B, Ridley AJ (2011) Identification and characterization of a set of conserved and new regulators of cytoskeletal organization, cell morphology and migration. BMC Biol 9:54PubMedPubMedCentral

Bao J, Wu Y, Zhang K, Qi H (2022) AC099850.3/NCAPG axis predicts poor prognosis and is associated with resistance to EGFR tyrosine-kinase inhibitors in lung adenocarcinoma. Int J General Med 15:6917–6930

Barrett T, Wilhite SE, Ledoux P, Evangelista C, Kim IF, Tomashevsky M, Marshall KA, Phillippy KH, Sherman PM, Holko M, Yefanov A, Lee H, Zhang N, Robertson CL, Serova N, Davis S, Soboleva A (2013) NCBI GEO: archive for functional genomics data sets–update. Nucleic Acids Res 41(Database issue):D991–D995PubMed

Chen Z, Chen Q, Cheng Z, Gu J, Feng W, Lei T, Huang J, Pu J, Chen X, Wang Z (2020) Long non-coding RNA CASC9 promotes gefitinib resistance in NSCLC by epigenetic repression of DUSP1. Cell Death Dis 11(10):858PubMedPubMedCentral

Cheng Y, He Y, Li W, Zhang HL, Zhou Q, Wang B, Liu C, Walding A, Saggese M, Huang X, Fan M, Wang J, Ramalingam SS (2021) Osimertinib versus comparator EGFR TKI as first-line treatment for EGFR-mutated advanced NSCLC: FLAURA China, a randomized study. Target Oncol 16(2):165–176PubMedPubMedCentral

Cui C, Wang J, Fagerberg E, Chen P-M, Connolly KA, Damo M, Cheung JF, Mao T, Askari AS, Chen S, Fitzgerald B, Foster GG, Eisenbarth SC, Zhao H, Craft J, Joshi NS (2021) Neoantigen-driven B cell and CD4 T follicular helper cell collaboration promotes anti-tumor CD8 T cell responses. Cell 184(25):6101-6118.e13PubMedPubMedCentral

Cui J, Song Y, Han X, Hu J, Chen Y, Chen X, Xu X, Xing Y, Lu H, Cai L (2020) Targeting 14-3-3ζ overcomes resistance to epidermal growth factor receptor-tyrosine kinase inhibitors in lung adenocarcinoma via BMP2/Smad/ID1 signaling. Front Oncol 10:542007PubMedPubMedCentral

Darvin P, Toor SM, Sasidharan Nair V, Elkord E (2018) Immune checkpoint inhibitors: recent progress and potential biomarkers. Exp Mol Med 50(12):1–11PubMed

Fukuhara T, Saito H, Furuya N, Watanabe K, Sugawara S, Iwasawa S, Tsunezuka Y, Yamaguchi O, Okada PM, Yoshimori K, Nakachi I, Gemma PA, Azuma K, Kurimoto F, Tsubata Y, Fujita Y, Nagashima H, Asai G, Watanabe S, Miyazaki M, Hagiwara PK, Nukiwa PT, Morita PS, Kobayashi PK, Maemondo PM (2020) Evaluation of plasma EGFR mutation as an early predictor of response of erlotinib plus bevacizumab treatment in the NEJ026 study. EBioMedicine 57:102861PubMedPubMedCentral

Grisaru-Tal S, Itan M, Klion AD, Munitz A (2020) A new dawn for eosinophils in the tumour microenvironment. Nat Rev Cancer 20(10):594–607PubMed

Guillerey C, Huntington ND, Smyth MJ (2016) Targeting natural killer cells in cancer immunotherapy. Nat Immunol 17(9):1025–1036PubMed

Jiang P, Gu S, Pan D, Fu J, Sahu A, Hu X, Li Z, Traugh N, Bu X, Li B, Liu J, Freeman GJ, Brown MA, Wucherpfennig KW, Liu XS (2018) Signatures of T cell dysfunction and exclusion predict cancer immunotherapy response. Nat Med 24(10):1550–1558PubMedPubMedCentral

Khaddour K, Jonna S, Deneka A, Patel JD, Abazeed ME, Golemis E, Borghaei H, Boumber Y (2021) Targeting the epidermal growth factor receptor in EGFR-mutated lung cancer: current and emerging therapies. Cancers (basel) 13(13):3164PubMed

Koren A, Rijavec M, Krumpestar T, Kern I, Sadikov A, Čufer T, Korošec P (2021) Gene expression levels of the prolyl hydroxylase domain proteins PHD1 and PHD2 but not PHD3 are decreased in primary tumours and correlate with poor prognosis of patients with surgically resected non-small-cell lung cancer. Cancers (basel) 13(10):2309PubMed

Lee S, Jung J, Lee YJ, Kim SK, Kim JA, Kim BK, Park KC, Kwon BM, Han DC (2021) Targeting HSF1 as a therapeutic strategy for multiple mechanisms of EGFR inhibitor resistance in EGFR mutant non-small-cell lung cancer. Cancers (basel) 13(12):2987PubMedPubMedCentral

Lefebvre C, Bachelot T, Filleron T, Pedrero M, Campone M, Soria JC, Massard C, Lévy C, Arnedos M, Lacroix-Triki M, Garrabey J, Boursin Y, Deloger M, Fu Y, Commo F, Scott V, Lacroix L, Dieci MV, Kamal M, Diéras V, Gonçalves A, Ferrerro JM, Romieu G, Vanlemmens L, Mouret Reynier MA, Théry JC, Le Du F, Guiu S, Dalenc F, Clapisson G, Bonnefoi H, Jimenez M, Le Tourneau C, André F (2016) Mutational profile of metastatic breast cancers: a retrospective analysis. PLoS Med 13(12):e1002201PubMedPubMedCentral

Lei X, Lei Y, Li JK, Du WX, Li RG, Yang J, Li J, Li F, Tan HB (2020) Immune cells within the tumor microenvironment: biological functions and roles in cancer immunotherapy. Cancer Lett 470:126–133PubMed

Lin L, Cheng J, Tang D, Zhang Y, Zhang F, Xu J, Jiang H, Wu H (2020) The associations among quantitative spectral CT parameters, Ki-67 expression levels and EGFR mutation status in NSCLC. Sci Rep 10(1):3436PubMedPubMedCentral

Litchfield K, Summersgill B, Yost S, Sultana R, Labreche K, Dudakia D, Renwick A, Seal S, Al-Saadi R, Broderick P, Turner NC, Houlston RS, Huddart R, Shipley J, Turnbull C (2015) Whole-exome sequencing reveals the mutational spectrum of testicular germ cell tumours. Nat Commun 6:5973PubMedPubMedCentral

Liu W, Wu H, Wang L, Yang X, Liu C, He X, Li W, Wang J, Chen Y, Wang H, Gao Y, Tang S, Yang S, Jin L, Zhang F, Cao Y (2019) Homozygous loss-of-function mutations in FSIP2 cause male infertility with asthenoteratospermia. J Genet Genom 46(1):53–56

Madsen CD, Hooper S, Tozluoglu M, Bruckbauer A, Fletcher G, Erler JT, Bates PA, Thompson B, Sahai E (2015) STRIPAK components determine mode of cancer cell migration and metastasis. Nat Cell Biol 17(1):68–80PubMed

Maeser D, Gruener RF, Huang RS (2021) oncoPredict: an R package for predicting in vivo or cancer patient drug response and biomarkers from cell line screening data. Brief Bioinform 22(6):bbab260PubMedPubMedCentral

Newman AM, Liu CL, Green MR, Gentles AJ, Feng W, Xu Y, Hoang CD, Diehn M, Alizadeh AA (2015) Robust enumeration of cell subsets from tissue expression profiles. Nat Methods 12(5):453–457PubMedPubMedCentral

Qiu L-M, Sun Y-H, Chen T-T, Chen J-J, Ma H-T (2020) STRIP2, a member of the striatin-interacting phosphatase and kinase complex, is implicated in lung adenocarcinoma cell growth and migration. FEBS Open Bio 10(3):351–361PubMedPubMedCentral

Ramalingam SS, Vansteenkiste J, Planchard D, Cho BC, Gray JE, Ohe Y, Zhou C, Reungwetwattana T, Cheng Y, Chewaskulyong B, Shah R, Cobo M, Lee KH, Cheema P, Tiseo M, John T, Lin M-C, Imamura F, Kurata T, Todd A, Hodge R, Saggese M, Rukazenkov Y, Soria J-C (2020) Overall survival with osimertinib in untreated, -mutated advanced NSCLC. N Engl J Med 382(1):41–50PubMed

Shah N, Wang P, Wongvipat J, Karthaus WR, Abida W, Armenia J, Rockowitz S, Drier Y, Bernstein BE, Long HW, Freedman ML, Arora VK, Zheng D, Sawyers CL (2017) Regulation of the glucocorticoid receptor via a BET-dependent enhancer drives antiandrogen resistance in prostate cancer. Elife 6:e27861PubMedPubMedCentral

Shang Y, Li X, Liu W, Shi X, Yuan S, Huo R, Fang G, Han X, Zhang J, Wang K, Dou Z, Zhang Y, Zang A, Zhang L (2020) Comprehensive genomic profile of Chinese lung cancer patients and mutation characteristics of individuals resistant to icotinib/gefitinib. Sci Rep 10(1):20243PubMedPubMedCentral

Shi Y, Xu Y, Xu Z, Wang H, Zhang J, Wu Y, Tang B, Zheng S, Wang K (2022) TKI resistant-based prognostic immune related gene signature in LUAD, in which FSCN1 contributes to tumor progression. Cancer Lett 532:215583PubMed

Shi Z, Jiao S, Zhou Z (2016) STRIPAK complexes in cell signaling and cancer. Oncogene 35(35):4549–4557PubMed

Shiiya A, Noguchi T, Tomaru U, Ariga S, Takashima Y, Ohhara Y, Taguchi J, Takeuchi S, Shimizu Y, Kinoshita I, Koizumi T, Matsuno Y, Shinagawa N, Sakakibara-Konishi J, Dosaka-Akita H (2023) EGFR inhibition in EGFR-mutant lung cancer cells perturbs innate immune signaling pathways in the tumor microenvironment. Cancer Sci 114:12270–21283

Song C, Pan S, Li D, Hao B, Lu Z, Lai K, Li N, Geng Q (2022) Comprehensive analysis reveals the potential value of inflammatory response genes in the prognosis, immunity, and drug sensitivity of lung adenocarcinoma. BMC Med Genom 15(1):198

Sun J, Zhang Q, Sun X, Xue A, Gao X, Shen K (2022) THZ1 targeting CDK7 suppresses c-KIT transcriptional activity in gastrointestinal stromal tumours. Cell Commun Signal 20(1):138PubMedPubMedCentral

Takashima Y, Sakakibara-Konishi J, Hatanaka Y, Hatanaka KC, Ohhara Y, Oizumi S, Hida Y, Kaga K, Kinoshita I, Dosaka-Akita H, Matsuno Y, Nishimura M (2018) Clinicopathologic features and immune microenvironment of non-small-cell lung cancer with primary resistance to epidermal growth factor receptor tyrosine kinase inhibitors. Clin Lung Cancer 19(4):352-359.e1PubMed

Tang Z, Li C, Kang B, Gao G, Li C, Zhang Z (2017) GEPIA: a web server for cancer and normal gene expression profiling and interactive analyses. Nucleic Acids Res 45(W1):W98–W102PubMedPubMedCentral

Uramoto H, Shimokawa H, Hanagiri T, Kuwano M, Ono M (2011) Expression of selected gene for acquired drug resistance to EGFR-TKI in lung adenocarcinoma. Lung Cancer 73(3):361–365PubMed

Voskoboinik I, Smyth MJ, Trapani JA (2006) Perforin-mediated target-cell death and immune homeostasis. Nat Rev Immunol 6(12):940–952PubMed

Wang R, Yamada T, Kita K, Taniguchi H, Arai S, Fukuda K, Terashima M, Ishimura A, Nishiyama A, Tanimoto A, Takeuchi S, Ohtsubo K, Yamashita K, Yamano T, Yoshimura A, Takayama K, Kaira K, Taniguchi Y, Atagi S, Uehara H, Hanayama R, Matsumoto I, Han X, Matsumoto K, Wang W, Suzuki T, Yano S (2020a) Transient IGF-1R inhibition combined with osimertinib eradicates AXL-low expressing EGFR mutated lung cancer. Nat Commun 11(1):4607PubMedPubMedCentral

Wang X, Li X, Guo H, Zhu L, Peng Z, Wang J, Yang F, Guo Y (2020b) Highly sensitive droplet digital PCR method for detection of de novo EGFR T790M mutation in patients with non-small cell lung cancer. Onco Targets Ther 13:10621–10630PubMedPubMedCentral

Xia L, Yang F, Wu X, Li S, Kan C, Zheng H, Wang S (2021) SHP2 inhibition enhances the anticancer effect of osimertinib in EGFR T790M mutant lung adenocarcinoma by blocking CXCL8 loop mediated stemness. Cancer Cell Int 21(1):337PubMedPubMedCentral

Yonesaka K, Iwama E, Hayashi H, Suzuki S, Kato R, Watanabe S, Takahama T, Tanizaki J, Tanaka K, Takeda M, Sakai K, Azuma K, Chiba Y, Atagi S, Nishio K, Okamoto I, Nakagawa K (2019) Heregulin expression and its clinical implication for patients with EGFR-mutant non-small cell lung cancer treated with EGFR-tyrosine kinase inhibitors. Sci Rep 9(1):19501PubMedPubMedCentral

Zhang T, Sun B, Zhong C, Xu K, Wang Z, Hofman P, Nagano T, Legras A, Breadner D, Ricciuti B, Divisi D, Schmid RA, Peng RW, Yang H, Yao F (2021) Targeting histone deacetylase enhances the therapeutic effect of Erastin-induced ferroptosis in EGFR-activating mutant lung adenocarcinoma. Transl Lung Cancer Res 10(4):1857–1872PubMedPubMedCentral

Zhang W, Lin Z, Shi F, Wang Q, Kong Y, Ren Y, Lyu J, Sheng C, Li Y, Qin H, Wang S, Wang Q (2022) HSPG2 mutation association with immune checkpoint inhibitor outcome in melanoma and non-small cell lung cancer. Cancers (basel) 14(14):3495PubMed

Zhang X, Chen Q, He Y, Shi Q, Yin C, Xie Y, Yu H, Bao Y, Wang X, Tang C, Dong Z (2023) STRIP2 motivates non-small cell lung cancer progression by modulating the TMBIM6 stability through IGF2BP3 dependent. J Exp Clin Cancer Res 42(1):19PubMedPubMedCentral

Zhang Y, Zhu X, Qiao X, Sun L, Tian Y, Yang Y, Zhao Y, Liu C (2020) FSIP2 can serve as a predictive biomarker for clear cell renal cell carcinoma prognosis. Int J Med Sci 17(17):2819–2825PubMedPubMedCentral

Titel: Osimertinib resistance prognostic gene signature: STRIP2 is associated with immune infiltration and tumor progression in lung adenocarcinoma
verfasst von: Guixing Zhang
Huiting Guan
Yi-Le Ning
Kainan Yao
Hao Tang
Gulizeba Muhetaer
Hang Li
Jihong Zhou
Publikationsdatum: 31.08.2023
Verlag: Springer Berlin Heidelberg
Erschienen in: Journal of Cancer Research and Clinical Oncology / Ausgabe 17/2023
Print ISSN: 0171-5216
Elektronische ISSN: 1432-1335
DOI: https://doi.org/10.1007/s00432-023-05294-w

Update Onkologie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen

Live-Webinar "Urologie und Sexualmedizin in der Praxis"

Springer Medizin

Osimertinib resistance prognostic gene signature: STRIP2 is associated with immune infiltration and tumor progression in lung adenocarcinoma

Abstract

Objective

Methods

Results

Conclusion

Graphical Abstract

Neu im Fachgebiet Onkologie

Bei seelischem Stress sind Checkpoint-Hemmer weniger wirksam

Erhebliches Risiko für Kehlkopfkrebs bei mäßiger Dysplasie

15% bedauern gewählte Blasenkrebs-Therapie

Erhöhtes Risiko fürs Herz unter Checkpointhemmer-Therapie

Update Onkologie

Live-Webinar "Urologie und Sexualmedizin in der Praxis"

Springer Medizin

Abstract

Objective

Methods

Results

Conclusion

Graphical Abstract

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 17/2023

Compatibility of the radical prostatectomy specimen findings with digital rectal examination

Selenium metabolism heterogeneity in pan-cancer: insights from bulk and single-cell RNA sequencing

Cordycepin improves sensitivity to temozolomide in glioblastoma cells by down-regulating MYC

Serum THBS2 is a potential biomarker for the diagnosis of non-small cell lung cancer

Circulating vitamin D concentration and risk of 14 cancers: a bidirectional Mendelian randomization study

KIF11 serves as a cell cycle mediator in childhood acute lymphoblastic leukemia

Neu im Fachgebiet Onkologie

Bei seelischem Stress sind Checkpoint-Hemmer weniger wirksam

Erhebliches Risiko für Kehlkopfkrebs bei mäßiger Dysplasie

15% bedauern gewählte Blasenkrebs-Therapie

Erhöhtes Risiko fürs Herz unter Checkpointhemmer-Therapie

Update Onkologie