دورية أكاديمية
Small-molecule targeted therapies induce dependence on DNA double-strand break repair in residual tumor cells.
العنوان: | Small-molecule targeted therapies induce dependence on DNA double-strand break repair in residual tumor cells. |
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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. |
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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 |
تدمد: | 1946-6242 |
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DOI: | 10.1126/scitranslmed.abc7480 |