دورية أكاديمية
أعرض في EDS

Small-molecule targeted therapies induce dependence on DNA double-strand break repair in residual tumor cells.

التفاصيل البيبلوغرافية
العنوان: Small-molecule targeted therapies induce dependence on DNA double-strand break repair in residual tumor cells.
المؤلفون: Ali M; Department of Pharmacology and Cancer Biology and Duke Cancer Institute, Duke University, Durham, NC 27710, USA., Lu M; Department of Pharmacology and Cancer Biology and Duke Cancer Institute, Duke University, Durham, NC 27710, USA., Ang HX; Department of Pharmacology and Cancer Biology and Duke Cancer Institute, Duke University, Durham, NC 27710, USA., Soderquist RS; Department of Pharmacology and Cancer Biology and Duke Cancer Institute, Duke University, Durham, NC 27710, USA., Eyler CE; Department of Pharmacology and Cancer Biology and Duke Cancer Institute, Duke University, Durham, NC 27710, USA., Hutchinson HM; Department of Pharmacology and Cancer Biology and Duke Cancer Institute, Duke University, Durham, NC 27710, USA., Glass C; Department of Pathology, Duke University, Durham, NC 27710, USA., Bassil CF; Department of Pharmacology and Cancer Biology and Duke Cancer Institute, Duke University, Durham, NC 27710, USA., Lopez OM; Department of Pharmacology and Cancer Biology and Duke Cancer Institute, Duke University, Durham, NC 27710, USA., Kerr DL; Department of Medicine and Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA., Falcon CJ; Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, NY 10065, USA., Yu HA; Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, NY 10065, USA., Hata AN; Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, MA 02129, USA., Blakely CM; Department of Medicine and Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA., McCoach CE; Department of Medicine and Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA., Bivona TG; Department of Medicine and Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA., Wood KC; Department of Pharmacology and Cancer Biology and Duke Cancer Institute, Duke University, Durham, NC 27710, USA.
المصدر: Science translational medicine [Sci Transl Med] 2022 Mar 30; Vol. 14 (638), pp. eabc7480. Date of Electronic Publication: 2022 Mar 30.
نوع المنشور: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: American Association for the Advancement of Science Country of Publication: United States NLM ID: 101505086 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1946-6242 (Electronic) Linking ISSN: 19466234 NLM ISO Abbreviation: Sci Transl Med Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Washington, DC : American Association for the Advancement of Science
مواضيع طبية MeSH: Carcinoma, Non-Small-Cell Lung*/drug therapy , Lung Neoplasms*/drug therapy, Animals ; DNA ; DNA Repair ; Humans ; Mice ; Neoplasm, Residual
مستخلص: Residual cancer cells that survive drug treatments with targeted therapies act as a reservoir from which eventual resistant disease emerges. Although there is great interest in therapeutically targeting residual cells, efforts are hampered by our limited knowledge of the vulnerabilities existing in this cell state. Here, we report that diverse oncogene-targeted therapies, including inhibitors of epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), KRAS, and BRAF, induce DNA double-strand breaks and, consequently, ataxia-telangiectasia mutated (ATM)-dependent DNA repair in oncogene-matched residual tumor cells. This DNA damage response, observed in cell lines, mouse xenograft models, and human patients, is driven by a pathway involving the activation of caspases 3 and 7 and the downstream caspase-activated deoxyribonuclease (CAD). CAD is, in turn, activated through caspase-mediated degradation of its endogenous inhibitor, ICAD. In models of EGFR mutant non-small cell lung cancer (NSCLC), tumor cells that survive treatment with small-molecule EGFR-targeted therapies are thus synthetically dependent on ATM, and combined treatment with an ATM kinase inhibitor eradicates these cells in vivo. This led to more penetrant and durable responses in EGFR mutant NSCLC mouse xenograft models, including those derived from both established cell lines and patient tumors. Last, we found that rare patients with EGFR mutant NSCLC harboring co-occurring, loss-of-function mutations in ATM exhibit extended progression-free survival on first generation EGFR inhibitor therapy relative to patients with EGFR mutant NSCLC lacking deleterious ATM mutations. Together, these findings establish a rationale for the mechanism-based integration of ATM inhibitors alongside existing targeted therapies.
References: Nat Commun. 2015 Sep 22;6:8305. (PMID: 26392303)
Cancer Discov. 2015 May;5(5):475-87. (PMID: 25895919)
Cancer Discov. 2012 Nov;2(11):1048-63. (PMID: 22915751)
Cell Rep. 2017 Dec 5;21(10):2796-2812. (PMID: 29212027)
Clin Cancer Res. 2013 Apr 15;19(8):2240-7. (PMID: 23470965)
Sci Transl Med. 2017 May 31;9(392):. (PMID: 28566428)
Nature. 2017 Nov 9;551(7679):247-250. (PMID: 29088702)
Sci Adv. 2018 Jun 20;4(6):eaat1719. (PMID: 29938225)
Mol Cell. 2013 Sep 26;51(6):751-65. (PMID: 24074954)
Cancer Res. 2010 Jan 15;70(2):440-6. (PMID: 20068163)
Nat Med. 2016 Mar;22(3):262-9. (PMID: 26828195)
BMC Cancer. 2013 Dec 21;13:604. (PMID: 24359526)
Cell Res. 2017 Jun;27(6):764-783. (PMID: 28337983)
Nat Med. 2016 May 5;22(5):472-8. (PMID: 27149220)
Cancer Discov. 2015 Sep;5(9):960-971. (PMID: 26036643)
Cancer Discov. 2019 May;9(5):587-604. (PMID: 30992280)
Nat Genet. 2020 Apr;52(4):408-417. (PMID: 32203462)
Cell. 2011 Apr 1;145(1):19-24. (PMID: 21458664)
Science. 2014 Jan 3;343(6166):84-87. (PMID: 24336571)
Cell. 2010 Apr 2;141(1):69-80. (PMID: 20371346)
Trends Cancer. 2019 Mar;5(3):170-182. (PMID: 30898264)
Cancer Discov. 2017 Jul 20;:. (PMID: 28729406)
Cell. 2018 May 31;173(6):1413-1425.e14. (PMID: 29754815)
Cell. 2016 Mar 24;165(1):234-246. (PMID: 26924578)
Lancet Oncol. 2019 Apr;20(4):570-580. (PMID: 30880072)
Cell Rep. 2019 Jun 18;27(12):3422-3432.e4. (PMID: 31216465)
Nat Commun. 2017 Jun 08;8:15617. (PMID: 28593995)
Trends Cancer. 2018 Nov;4(11):755-768. (PMID: 30352678)
Nat Commun. 2018 Apr 26;9(1):1677. (PMID: 29700304)
Science. 2014 Dec 19;346(6216):1480-6. (PMID: 25394791)
Science. 2019 Dec 20;366(6472):1473-1480. (PMID: 31699882)
Science. 2014 Jan 3;343(6166):80-4. (PMID: 24336569)
Nature. 2017 Jul 27;547(7664):453-457. (PMID: 28678785)
Biomedicine (Taipei). 2015 Nov;5(4):19. (PMID: 26613930)
Mol Cancer Ther. 2017 Dec;16(12):2645-2655. (PMID: 29203694)
Cancer Discov. 2019 Apr;9(4):526-545. (PMID: 30709805)
Cancer Discov. 2012 Nov;2(11):1036-47. (PMID: 22915752)
معلومات مُعتمدة: U01 CA217882 United States CA NCI NIH HHS; F32 CA206234 United States CA NCI NIH HHS; U54 CA224081 United States CA NCI NIH HHS; R01 CA211052 United States CA NCI NIH HHS; P30 CA008748 United States CA NCI NIH HHS; F30 CA220847 United States CA NCI NIH HHS; R01 CA207083 United States CA NCI NIH HHS; T32 GM007171 United States GM NIGMS NIH HHS; R01 CA204302 United States CA NCI NIH HHS; P30 CA014236 United States CA NCI NIH HHS; T32 GM145449 United States GM NIGMS NIH HHS; R01 CA231300 United States CA NCI NIH HHS; R01 CA169338 United States CA NCI NIH HHS
المشرفين على المادة: 9007-49-2 (DNA)
تواريخ الأحداث: Date Created: 20220330 Date Completed: 20220401 Latest Revision: 20230906
رمز التحديث: 20231215
مُعرف محوري في PubMed: PMC9516479
DOI: 10.1126/scitranslmed.abc7480
PMID: 35353542
قاعدة البيانات: MEDLINE
الوصف
تدمد:1946-6242
DOI:10.1126/scitranslmed.abc7480