دورية أكاديمية
Combined Inhibition of STAT3 and DNA Repair in Palbociclib-Resistant ER-Positive Breast Cancer.
| العنوان: | Combined Inhibition of STAT3 and DNA Repair in Palbociclib-Resistant ER-Positive Breast Cancer. |
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| المؤلفون: | Kettner NM; Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. kkeyomar@mdanderson.org NMKettner@mdanderson.org., Vijayaraghavan S; Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Durak MG; Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Bui T; Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Kohansal M; Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Ha MJ; Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas., Liu B; Department of Human Genetics, The University of Texas MD Anderson Cancer Center, Houston, Texas., Rao X; Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Wang J; Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Yi M; Department of Breast Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Carey JPW; Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Chen X; Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Eckols TK; Department of Infectious Diseases, Infection Control & Employee Health, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas., Raghavendra AS; Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Ibrahim NK; Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Karuturi MS; Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Watowich SS; Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Sahin A; Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Tweardy DJ; Department of Infectious Diseases, Infection Control & Employee Health, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.; Department of Molecular & Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Hunt KK; Department of Breast Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Tripathy D; Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Keyomarsi K; Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. kkeyomar@mdanderson.org NMKettner@mdanderson.org. |
| المصدر: | Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2019 Jul 01; Vol. 25 (13), pp. 3996-4013. Date of Electronic Publication: 2019 Mar 13. |
| نوع المنشور: | Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S. |
| اللغة: | English |
| بيانات الدورية: | Publisher: The Association Country of Publication: United States NLM ID: 9502500 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1557-3265 (Electronic) Linking ISSN: 10780432 NLM ISO Abbreviation: Clin Cancer Res Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Denville, NJ : The Association, c1995- |
| مواضيع طبية MeSH: | Drug Resistance, Neoplasm*, Antineoplastic Combined Chemotherapy Protocols/*therapeutic use , Breast Neoplasms/*drug therapy , Breast Neoplasms/*metabolism , DNA Repair/*drug effects , Receptors, Estrogen/*metabolism , STAT3 Transcription Factor/*antagonists & inhibitors, Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; Antineoplastic Combined Chemotherapy Protocols/adverse effects ; Breast Neoplasms/pathology ; Cell Line, Tumor ; Computational Biology/methods ; Epithelial-Mesenchymal Transition/genetics ; Female ; Gene Expression Profiling ; Humans ; Immunohistochemistry ; Piperazines/pharmacology ; Piperazines/therapeutic use ; Protein Kinase Inhibitors/pharmacology ; Pyridines/pharmacology ; Pyridines/therapeutic use ; Treatment Outcome |
| مستخلص: | Purpose: Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors are currently used in combination with endocrine therapy to treat advanced hormone receptor-positive, HER2-negative breast cancer. Although this treatment doubles time to progression compared with endocrine therapy alone, about 25%-35% of patients do not respond, and almost all patients eventually acquire resistance. Discerning the mechanisms of resistance to CDK4/6 inhibition is crucial in devising alternative treatment strategies. Experimental Design: Palbociclib-resistant cells (MCF-7 and T47D) were generated in a step-wise dose-escalading fashion. Whole-exome sequencing, genome-wide expression analysis, and proteomic analysis were performed in both resistant and parental (sensitive) cells. Pathway alteration was assessed mechanistically and pharmacologically. Biomarkers of altered pathways were examined in tumor samples from patients with palbociclib-treated breast cancer whose disease progressed while on treatment. Results: Palbociclib-resistant cells are cross-resistant to other CDK4/6 inhibitors and are also resistant to endocrine therapy (estrogen receptor downregulation). IL6/STAT3 pathway is induced, whereas DNA repair and estrogen receptor pathways are downregulated in the resistant cells. Combined inhibition of STAT3 and PARP significantly increased cell death in the resistant cells. Matched tumor samples from patients with breast cancer who progressed on palbociclib were examined for deregulation of estrogen receptor, DNA repair, and IL6/STAT3 signaling, and results revealed that these pathways are all altered as compared with the pretreatment tumor samples. Conclusions: Palbociclib resistance induces endocrine resistance, estrogen receptor downregulation, and alteration of IL6/STAT3 and DNA damage response pathways in cell lines and patient samples. Targeting IL6/STAT3 activity and DNA repair deficiency using a specific STAT3 inhibitor combined with a PARP inhibitor could effectively treat acquired resistance to palbociclib. (©2019 American Association for Cancer Research.) |
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| معلومات مُعتمدة: | R01 AI109294 United States AI NIAID NIH HHS; P30 CA016672 United States CA NCI NIH HHS; R01 CA152228 United States CA NCI NIH HHS; R56 AI109294 United States AI NIAID NIH HHS; R01 CA223772 United States CA NCI NIH HHS |
| المشرفين على المادة: | 0 (Antineoplastic Agents) 0 (Piperazines) 0 (Protein Kinase Inhibitors) 0 (Pyridines) 0 (Receptors, Estrogen) 0 (STAT3 Transcription Factor) 0 (STAT3 protein, human) G9ZF61LE7G (palbociclib) |
| تواريخ الأحداث: | Date Created: 20190315 Date Completed: 20200805 Latest Revision: 20231108 |
| رمز التحديث: | 20231108 |
| مُعرف محوري في PubMed: | PMC6606366 |
| DOI: | 10.1158/1078-0432.CCR-18-3274 |
| PMID: | 30867218 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1557-3265 |
|---|---|
| DOI: | 10.1158/1078-0432.CCR-18-3274 |