Login Register Cart 0
Generic placeholder image

Current Cancer Drug Targets

Editor-in-Chief

ISSN (Print): 1568-0096
ISSN (Online): 1873-5576

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Identification of ATM Mutation as a Potential Prognostic Biomarker for Immune Checkpoint Inhibitors Therapy

Author(s): Saijin Cui, Tianyu Chen, Yaning Zhao, Zhuoyun Xiao, Meitong Liu, Xi Huang, Shiru Cao, Rongmiao Zhou, You Li, Xiangran Huo and Na Wang*

Volume 24, Issue 5, 2024

Published on: 20 November, 2023

Page: [501 - 509] Pages: 9

DOI: 10.2174/0115680096250376231025062652

Price: $65

Abstract

Background: Ataxia telangiectasia mutated (ATM), an apical DNA damage response gene, is a commonly mutated gene in tumors, and its mutation could strengthen tumor immunogenicity and alter the expression of PD-L1, which potentially contributes to immune checkpoint inhibitors (ICIs) therapy.

Methods: The characteristics of ATM mutation and its relationship with the ICIs-treated clinical prognosis have been analyzed comprehensively in this paper. The overall frequency of ATM mutations has been found to be 4% (554/10953) in the cancer genome atlas (TCGA) cohort.

Results: Both the TMB and MSI levels in patients with ATM mutations were significantly higher than those in patients without mutations (P < 0.0001). The median TMB was positively correlated with the frequency of ATM mutations (r = 0.54, P = 0.003). In the TCGA cohort, patients with ATM mutations had better clinical benefits in terms of overall survival (OS, hazard ratio (HR) = 0.736, 95% CI = 0.623 - 0.869), progression-free survival (PFS, HR = 0.761, 95% CI = 0.652 - 0.889), and disease-free survival (DFS, HR = 0.686, 95% CI = 0.512 - 0.919)] than patients without ATM mutations. Subsequently, the verification results showed ATM mutations to be significantly correlated with longer OS in ICIs-treated patients (HR = 0.710, 95% CI = 0.544 - 0.928). Further exploration indicated ATM mutation to be significantly associated with regulated anti-tumor immunity (P < 0.05).

Conclusion: Our findings highlight the value of ATM mutation as a promising biomarker to predict ICIs therapy in multiple tumors.

« Previous Next »
Graphical Abstract

[1]
Kraehenbuehl, L.; Weng, C.H.; Eghbali, S.; Wolchok, J.D.; Merghoub, T. Enhancing immunotherapy in cancer by targeting emerging immunomodulatory pathways. Nat. Rev. Clin. Oncol., 2022, 19(1), 37-50.
[http://dx.doi.org/10.1038/s41571-021-00552-7] [PMID: 34580473]
[2]
Bagchi, S.; Yuan, R.; Engleman, E.G. Immune checkpoint inhibitors for the treatment of cancer: Clinical impact and mechanisms of response and resistance. Annu. Rev. Pathol., 2021, 16(1), 223-249.
[http://dx.doi.org/10.1146/annurev-pathol-042020-042741] [PMID: 33197221]
[3]
Hegde, P.S.; Chen, D.S. Top 10 challenges in cancer immunotherapy. Immunity, 2020, 52(1), 17-35.
[http://dx.doi.org/10.1016/j.immuni.2019.12.011] [PMID: 31940268]
[4]
Ueno, S.; Sudo, T.; Hirasawa, A. ATM: Functions of ATM kinase and its relevance to hereditary tumors. Int. J. Mol. Sci., 2022, 23(1), 523.
[http://dx.doi.org/10.3390/ijms23010523] [PMID: 35008949]
[5]
Ali, M.; Lu, M.; Ang, H.X.; Soderquist, R.S.; Eyler, C.E.; Hutchinson, H.M.; Glass, C.; Bassil, C.F.; Lopez, O.M.; Kerr, D.L.; Falcon, C.J.; Yu, H.A.; Hata, A.N.; Blakely, C.M.; McCoach, C.E.; Bivona, T.G.; Wood, K.C. Small-molecule targeted therapies induce dependence on DNA double-strand break repair in residual tumor cells. Sci. Transl. Med., 2022, 14(638), eabc7480.
[http://dx.doi.org/10.1126/scitranslmed.abc7480] [PMID: 35353542]
[6]
Hu, C.; Hart, S.N.; Polley, E.C.; Gnanaolivu, R.; Shimelis, H.; Lee, K.Y.; Lilyquist, J.; Na, J.; Moore, R.; Antwi, S.O.; Bamlet, W.R.; Chaffee, K.G.; DiCarlo, J.; Wu, Z.; Samara, R.; Kasi, P.M.; McWilliams, R.R.; Petersen, G.M.; Couch, F.J. Association between inherited germline mutations in cancer predisposition genes and risk of pancreatic cancer. JAMA, 2018, 319(23), 2401-2409.
[http://dx.doi.org/10.1001/jama.2018.6228] [PMID: 29922827]
[7]
Na, R.; Zheng, S.L.; Han, M.; Yu, H.; Jiang, D.; Shah, S.; Ewing, C.M.; Zhang, L.; Novakovic, K.; Petkewicz, J.; Gulukota, K.; Helseth, D.L., Jr; Quinn, M.; Humphries, E.; Wiley, K.E.; Isaacs, S.D.; Wu, Y.; Liu, X.; Zhang, N.; Wang, C.H.; Khandekar, J.; Hulick, P.J.; Shevrin, D.H.; Cooney, K.A.; Shen, Z.; Partin, A.W.; Carter, H.B.; Carducci, M.A.; Eisenberger, M.A.; Denmeade, S.R.; McGuire, M.; Walsh, P.C.; Helfand, B.T.; Brendler, C.B.; Ding, Q.; Xu, J.; Isaacs, W.B. Germline mutations in ATM and BRCA1/2 distinguish risk for lethal and indolent prostate cancer and are associated with early age at death. Eur. Urol., 2017, 71(5), 740-747.
[http://dx.doi.org/10.1016/j.eururo.2016.11.033] [PMID: 27989354]
[8]
Jiang, M.; Jia, K.; Wang, L.; Li, W.; Chen, B.; Liu, Y.; Wang, H.; Zhao, S.; He, Y.; Zhou, C. Alterations of DNA damage response pathway: Biomarker and therapeutic strategy for cancer immunotherapy. Acta Pharm. Sin. B, 2021, 11(10), 2983-2994.
[http://dx.doi.org/10.1016/j.apsb.2021.01.003] [PMID: 34729299]
[9]
Vidotto, T.; Nersesian, S.; Graham, C.; Siemens, D.R.; Koti, M. DNA damage repair gene mutations and their association with tumor immune regulatory gene expression in muscle invasive bladder cancer subtypes. J. Immunother. Cancer, 2019, 7(1), 148.
[http://dx.doi.org/10.1186/s40425-019-0619-8] [PMID: 31174611]
[10]
Härtlova, A.; Erttmann, S.F.; Raffi, F.A.M.; Schmalz, A.M.; Resch, U.; Anugula, S.; Lienenklaus, S.; Nilsson, L.M.; Kröger, A.; Nilsson, J.A.; Ek, T.; Weiss, S.; Gekara, N.O. DNA damage primes the type I interferon system via the cytosolic DNA sensor STING to promote anti-microbial innate immunity. Immunity, 2015, 42(2), 332-343.
[http://dx.doi.org/10.1016/j.immuni.2015.01.012] [PMID: 25692705]
[11]
Zhang, Q.; Green, M.D.; Lang, X.; Lazarus, J.; Parsels, J.D.; Wei, S.; Parsels, L.A.; Shi, J.; Ramnath, N.; Wahl, D.R.; Pasca di Magliano, M.; Frankel, T.L.; Kryczek, I.; Lei, Y.L.; Lawrence, T.S.; Zou, W.; Morgan, M.A. Inhibition of ATM increases interferon signaling and sensitizes pancreatic cancer to immune checkpoint blockade therapy. Cancer Res., 2019, 79(15), 3940-3951.
[http://dx.doi.org/10.1158/0008-5472.CAN-19-0761] [PMID: 31101760]
[12]
Goff, P.H.; Bhakuni, R.; Pulliam, T.; Lee, J.H.; Hall, E.T.; Nghiem, P. Intersection of two checkpoints: Could inhibiting the DNA damage response checkpoint rescue immune checkpoint-refractory cancer? Cancers, 2021, 13(14), 3415.
[http://dx.doi.org/10.3390/cancers13143415] [PMID: 34298632]
[13]
Gao, J.; Aksoy, B.A.; Dogrusoz, U.; Dresdner, G.; Gross, B.; Sumer, S.O.; Sun, Y.; Jacobsen, A.; Sinha, R.; Larsson, E.; Cerami, E.; Sander, C.; Schultz, N. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci. Signal., 2013, 6(269), pl1.
[http://dx.doi.org/10.1126/scisignal.2004088] [PMID: 23550210]
[14]
Miao, D.; Margolis, C.A.; Vokes, N.I.; Liu, D.; Taylor-Weiner, A.; Wankowicz, S.M.; Adeegbe, D.; Keliher, D.; Schilling, B.; Tracy, A.; Manos, M.; Chau, N.G.; Hanna, G.J.; Polak, P.; Rodig, S.J.; Signoretti, S.; Sholl, L.M.; Engelman, J.A.; Getz, G.; Jänne, P.A.; Haddad, R.I.; Choueiri, T.K.; Barbie, D.A.; Haq, R.; Awad, M.M.; Schadendorf, D.; Hodi, F.S.; Bellmunt, J.; Wong, K.K.; Hammerman, P.; Van Allen, E.M. Genomic correlates of response to immune checkpoint blockade in microsatellite-stable solid tumors. Nat. Genet., 2018, 50(9), 1271-1281.
[http://dx.doi.org/10.1038/s41588-018-0200-2] [PMID: 30150660]
[15]
Samstein, R.M.; Lee, C.H.; Shoushtari, A.N.; Hellmann, M.D.; Shen, R.; Janjigian, Y.Y.; Barron, D.A.; Zehir, A.; Jordan, E.J.; Omuro, A.; Kaley, T.J.; Kendall, S.M.; Motzer, R.J.; Hakimi, A.A.; Voss, M.H.; Russo, P.; Rosenberg, J.; Iyer, G.; Bochner, B.H.; Bajorin, D.F.; Al-Ahmadie, H.A.; Chaft, J.E.; Rudin, C.M.; Riely, G.J.; Baxi, S.; Ho, A.L.; Wong, R.J.; Pfister, D.G.; Wolchok, J.D.; Barker, C.A.; Gutin, P.H.; Brennan, C.W.; Tabar, V.; Mellinghoff, I.K.; DeAngelis, L.M.; Ariyan, C.E.; Lee, N.; Tap, W.D.; Gounder, M.M.; D’Angelo, S.P.; Saltz, L.; Stadler, Z.K.; Scher, H.I.; Baselga, J.; Razavi, P.; Klebanoff, C.A.; Yaeger, R.; Segal, N.H.; Ku, G.Y.; DeMatteo, R.P.; Ladanyi, M.; Rizvi, N.A.; Berger, M.F.; Riaz, N.; Solit, D.B.; Chan, T.A.; Morris, L.G.T. Tumor mutational load predicts survival after immunotherapy across multiple cancer types. Nat. Genet., 2019, 51(2), 202-206.
[http://dx.doi.org/10.1038/s41588-018-0312-8] [PMID: 30643254]
[16]
Liu, D.; Schilling, B.; Liu, D.; Sucker, A.; Livingstone, E.; Jerby-Arnon, L.; Zimmer, L.; Gutzmer, R.; Satzger, I.; Loquai, C.; Grabbe, S.; Vokes, N.; Margolis, C.A.; Conway, J.; He, M.X.; Elmarakeby, H.; Dietlein, F.; Miao, D.; Tracy, A.; Gogas, H.; Goldinger, S.M.; Utikal, J.; Blank, C.U.; Rauschenberg, R.; von Bubnoff, D.; Krackhardt, A.; Weide, B.; Haferkamp, S.; Kiecker, F.; Izar, B.; Garraway, L.; Regev, A.; Flaherty, K.; Paschen, A.; Van Allen, E.M.; Schadendorf, D. Integrative molecular and clinical modeling of clinical outcomes to PD1 blockade in patients with metastatic melanoma. Nat. Med., 2019, 25(12), 1916-1927.
[http://dx.doi.org/10.1038/s41591-019-0654-5] [PMID: 31792460]
[17]
Snyder, A.; Makarov, V.; Merghoub, T.; Yuan, J.; Zaretsky, J.M.; Desrichard, A.; Walsh, L.A.; Postow, M.A.; Wong, P.; Ho, T.S.; Hollmann, T.J.; Bruggeman, C.; Kannan, K.; Li, Y.; Elipenahli, C.; Liu, C.; Harbison, C.T.; Wang, L.; Ribas, A.; Wolchok, J.D.; Chan, T.A. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N. Engl. J. Med., 2014, 371(23), 2189-2199.
[http://dx.doi.org/10.1056/NEJMoa1406498] [PMID: 25409260]
[18]
Van Allen, E.M.; Miao, D.; Schilling, B.; Shukla, S.A.; Blank, C.; Zimmer, L.; Sucker, A.; Hillen, U.; Geukes Foppen, M.H.; Goldinger, S.M.; Utikal, J.; Hassel, J.C.; Weide, B.; Kaehler, K.C.; Loquai, C.; Mohr, P.; Gutzmer, R.; Dummer, R.; Gabriel, S.; Wu, C.J.; Schadendorf, D.; Garraway, L.A. Genomic correlates of response to CTLA-4 blockade in metastatic melanoma. Science, 2015, 350(6257), 207-211.
[http://dx.doi.org/10.1126/science.aad0095] [PMID: 26359337]
[19]
Janjigian, Y.Y.; Sanchez-Vega, F.; Jonsson, P.; Chatila, W.K.; Hechtman, J.F.; Ku, G.Y.; Riches, J.C.; Tuvy, Y.; Kundra, R.; Bouvier, N.; Vakiani, E.; Gao, J.; Heins, Z.J.; Gross, B.E.; Kelsen, D.P.; Zhang, L.; Strong, V.E.; Schattner, M.; Gerdes, H.; Coit, D.G.; Bains, M.; Stadler, Z.K.; Rusch, V.W.; Jones, D.R.; Molena, D.; Shia, J.; Robson, M.E.; Capanu, M.; Middha, S.; Zehir, A.; Hyman, D.M.; Scaltriti, M.; Ladanyi, M.; Rosen, N.; Ilson, D.H.; Berger, M.F.; Tang, L.; Taylor, B.S.; Solit, D.B.; Schultz, N. Genetic predictors of response to systemic therapy in esophagogastric cancer. Cancer Discov., 2018, 8(1), 49-58.
[http://dx.doi.org/10.1158/2159-8290.CD-17-0787] [PMID: 29122777]
[20]
Ru, B.; Wong, C.N.; Tong, Y.; Zhong, J.Y.; Zhong, S.S.W.; Wu, W.C.; Chu, K.C.; Wong, C.Y.; Lau, C.Y.; Chen, I.; Chan, N.W.; Zhang, J. TISIDB: An integrated repository portal for tumor–immune system interactions. Bioinformatics, 2019, 35(20), 4200-4202.
[http://dx.doi.org/10.1093/bioinformatics/btz210] [PMID: 30903160]
[21]
Huang, R.; Zhou, P.K. DNA damage repair: Historical perspectives, mechanistic pathways and clinical translation for targeted cancer therapy. Signal Transduct. Target. Ther., 2021, 6(1), 254.
[http://dx.doi.org/10.1038/s41392-021-00648-7] [PMID: 34238917]
[22]
Hall, M.J.; Bernhisel, R.; Hughes, E.; Larson, K.; Rosenthal, E.T.; Singh, N.A.; Lancaster, J.M.; Kurian, A.W. Germline pathogenic variants in the ataxia telangiectasia mutated ( ATM ) gene are associated with high and moderate risks for multiple cancers. Cancer Prev. Res., 2021, 14(4), 433-440.
[http://dx.doi.org/10.1158/1940-6207.CAPR-20-0448] [PMID: 33509806]
[23]
van Os, N.J.H.; Roeleveld, N.; Weemaes, C.M.R.; Jongmans, M.C.J.; Janssens, G.O.; Taylor, A.M.R.; Hoogerbrugge, N.; Willemsen, M.A.A.P. Health risks for ataxia-telangiectasia mutated heterozygotes: A systematic review, meta-analysis and evidence-based guideline. Clin. Genet., 2016, 90(2), 105-117.
[http://dx.doi.org/10.1111/cge.12710] [PMID: 26662178]
[24]
Choi, M.; Kipps, T.; Kurzrock, R. ATM mutations in cancer: Therapeutic implications. Mol. Cancer Ther., 2016, 15(8), 1781-1791.
[http://dx.doi.org/10.1158/1535-7163.MCT-15-0945] [PMID: 27413114]
[25]
Camacho, E.; Hernández, L.; Hernández, S.; Tort, F.; Bellosillo, B.; Beà, S.; Bosch, F.; Montserrat, E.; Cardesa, A.; Fernández, P.L.; Campo, E. ATM gene inactivation in mantle cell lymphoma mainly occurs by truncating mutations and missense mutations involving the phosphatidylinositol-3 kinase domain and is associated with increasing numbers of chromosomal imbalances. Blood, 2002, 99(1), 238-244.
[http://dx.doi.org/10.1182/blood.V99.1.238] [PMID: 11756177]
[26]
Byrski, T.; Dent, R.; Blecharz, P.; Foszczynska-Kloda, M.; Gronwald, J.; Huzarski, T.; Cybulski, C.; Marczyk, E.; Chrzan, R.; Eisen, A.; Lubinski, J.; Narod, S.A. Results of a phase II open-label, non-randomized trial of cisplatin chemotherapy in patients with BRCA1-positive metastatic breast cancer. Breast Cancer Res., 2012, 14(4), R110.
[http://dx.doi.org/10.1186/bcr3231] [PMID: 22817698]
[27]
Lee, J.; Ledermann, J.A.; Kohn, E.C. PARP inhibitors for BRCA1/2 mutation-associated and BRCA-like malignancies. Ann. Oncol., 2014, 25(1), 32-40.
[http://dx.doi.org/10.1093/annonc/mdt384] [PMID: 24225019]
[28]
Chabanon, R.M.; Rouanne, M.; Lord, C.J.; Soria, J.C.; Pasero, P.; Postel-Vinay, S. Targeting the DNA damage response in immuno-oncology: developments and opportunities. Nat. Rev. Cancer, 2021, 21(11), 701-717.
[http://dx.doi.org/10.1038/s41568-021-00386-6] [PMID: 34376827]
[29]
Russell, R.; Perkhofer, L.; Liebau, S.; Lin, Q.; Lechel, A.; Feld, F.M.; Hessmann, E.; Gaedcke, J.; Güthle, M.; Zenke, M.; Hartmann, D.; von Figura, G.; Weissinger, S.E.; Rudolph, K.L.; Möller, P.; Lennerz, J.K.; Seufferlein, T.; Wagner, M.; Kleger, A. Loss of ATM accelerates pancreatic cancer formation and epithelial–mesenchymal transition. Nat. Commun., 2015, 6(1), 7677.
[http://dx.doi.org/10.1038/ncomms8677] [PMID: 26220524]
[30]
Hu, M.; Zhou, M.; Bao, X.; Pan, D.; Jiao, M.; Liu, X.; Li, F.; Li, C.Y. ATM inhibition enhances cancer immunotherapy by promoting mtDNA leakage and cGAS/STING activation. J. Clin. Invest., 2021, 131(3), e139333.
[http://dx.doi.org/10.1172/JCI139333] [PMID: 33290271]
[31]
Bule, P.; Aguiar, S.I.; Aires-Da-Silva, F.; Dias, J.N.R. Chemokine-directed tumor microenvironment modulation in cancer immunotherapy. Int. J. Mol. Sci., 2021, 22(18), 9804.
[http://dx.doi.org/10.3390/ijms22189804] [PMID: 34575965]
[32]
Susek, K.H.; Karvouni, M.; Alici, E.; Lundqvist, A. The role of CXC chemokine receptors 1–4 on immune cells in the tumor microenvironment. Front. Immunol., 2018, 9, 2159.
[http://dx.doi.org/10.3389/fimmu.2018.02159] [PMID: 30319622]
[33]
Keeley, E.C.; Mehrad, B.; Strieter, R.M. CXC chemokines in cancer angiogenesis and metastases. Adv. Cancer Res., 2010, 106, 91-111.
[http://dx.doi.org/10.1016/S0065-230X(10)06003-3] [PMID: 20399957]
[34]
Dangaj, D.; Bruand, M.; Grimm, A.J.; Ronet, C.; Barras, D.; Duttagupta, P.A.; Lanitis, E.; Duraiswamy, J.; Tanyi, J.L.; Benencia, F.; Conejo-Garcia, J.; Ramay, H.R.; Montone, K.T.; Powell, D.J., Jr; Gimotty, P.A.; Facciabene, A.; Jackson, D.G.; Weber, J.S.; Rodig, S.J.; Hodi, S.F.; Kandalaft, L.E.; Irving, M.; Zhang, L.; Foukas, P.; Rusakiewicz, S.; Delorenzi, M.; Coukos, G. Cooperation between constitutive and inducible chemokines enables T cell engraftment and immune attack in solid tumors. Cancer Cell, 2019, 35(6), 885-900.e10.
[http://dx.doi.org/10.1016/j.ccell.2019.05.004] [PMID: 31185212]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy