Phosphorylation of ribosomal protein S6 confers PARP inhibitor resistance in BRCA1-deficient cancers
Inhibition of poly(ADP-ribose) polymerase (PARP) is a promising therapeutic strategy for BRCA1 deficient cancers, however, the development of drug resistance limits clinical efficacy. Previously we found that the BRCA1-AKT1 pathway contributes to tumorigenesis and that the AKT1/mTOR is a novel thera...
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Published in | Oncotarget Vol. 5; no. 10; pp. 3375 - 3385 |
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Abstract | Inhibition of poly(ADP-ribose) polymerase (PARP) is a promising therapeutic strategy for BRCA1 deficient cancers, however, the development of drug resistance limits clinical efficacy. Previously we found that the BRCA1-AKT1 pathway contributes to tumorigenesis and that the AKT1/mTOR is a novel therapeutic target for BRCA1-deficient cancers. Here, we report that phosphorylation of ribosomal protein S6, a mTOR downstream effector, is greatly increased in BRCA1 deficient cells resistant to PARP inhibition. Phosphorylation of S6 is associated with DNA damage and repair signaling during PARP inhibitor treatment. In BRCA1 deficient cells, expression of S6 lacking all five phosphorylatable sites renders the cells sensitive to PARP inhibitor and increases DNA damage signals. In addition, the S6 mutations reduce tumor formation induced by Brca1-deficiency in mice. Inhibition of S6 phosphorylation by rapamycin restores PARP sensitivity to resistant cells. Combined treatment with rapamycin and PARP inhibitor effectively suppresses BRCA1-deficient tumor growth in mice. These results provide evidence for a novel mechanism by which BRCA1 deficient cancers acquire drug resistance and suggest a new therapeutic strategy to circumvent resistance. |
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AbstractList | Inhibition of poly(ADP-ribose) polymerase (PARP) is a promising therapeutic strategy for BRCA1 deficient cancers, however, the development of drug resistance limits clinical efficacy. Previously we found that the BRCA1-AKT1 pathway contributes to tumorigenesis and that the AKT1/mTOR is a novel therapeutic target for BRCA1-deficient cancers. Here, we report that phosphorylation of ribosomal protein S6, a mTOR downstream effector, is greatly increased in BRCA1 deficient cells resistant to PARP inhibition. Phosphorylation of S6 is associated with DNA damage and repair signaling during PARP inhibitor treatment. In BRCA1 deficient cells, expression of S6 lacking all five phosphorylatable sites renders the cells sensitive to PARP inhibitor and increases DNA damage signals. In addition, the S6 mutations reduce tumor formation induced by
Brca1
-deficiency in mice. Inhibition of S6 phosphorylation by rapamycin restores PARP sensitivity to resistant cells. Combined treatment with rapamycin and PARP inhibitor effectively suppresses
BRCA1
-deficient tumor growth in mice. These results provide evidence for a novel mechanism by which BRCA1 deficient cancers acquire drug resistance and suggest a new therapeutic strategy to circumvent resistance. Inhibition of poly(ADP-ribose) polymerase (PARP) is a promising therapeutic strategy for BRCA1 deficient cancers, however, the development of drug resistance limits clinical efficacy. Previously we found that the BRCA1-AKT1 pathway contributes to tumorigenesis and that the AKT1/mTOR is a novel therapeutic target for BRCA1-deficient cancers. Here, we report that phosphorylation of ribosomal protein S6, a mTOR downstream effector, is greatly increased in BRCA1 deficient cells resistant to PARP inhibition. Phosphorylation of S6 is associated with DNA damage and repair signaling during PARP inhibitor treatment. In BRCA1 deficient cells, expression of S6 lacking all five phosphorylatable sites renders the cells sensitive to PARP inhibitor and increases DNA damage signals. In addition, the S6 mutations reduce tumor formation induced by Brca1-deficiency in mice. Inhibition of S6 phosphorylation by rapamycin restores PARP sensitivity to resistant cells. Combined treatment with rapamycin and PARP inhibitor effectively suppresses BRCA1-deficient tumor growth in mice. These results provide evidence for a novel mechanism by which BRCA1 deficient cancers acquire drug resistance and suggest a new therapeutic strategy to circumvent resistance. |
Author | Huang, Yuping Yang, Qin Xiang, Tao Hu, Mickey C T Sun, Chong-kui Zhang, Fan Pandita, Tej K Chen, Qianming |
AuthorAffiliation | 3 Department of Radiation Oncology, UT Southwestern, Dallas, TX 75390 4 Research Biotechnology Business Unit, Sigma-Aldrich Corporation, St. Louis, MO 63103 2 State Key Laboratory of Oral Diseases, Sichuan University, Chengdu 610041, China 1 Cancer Biology Division, Department of Radiation Oncology, Washington University School of Medicine, Saint Louis, MO 63108 5 Division of Gynecologic Oncology, Department of Obstetrics & Gynecology, Stanford University School of Medicine, Stanford, CA 94305 |
AuthorAffiliation_xml | – name: 5 Division of Gynecologic Oncology, Department of Obstetrics & Gynecology, Stanford University School of Medicine, Stanford, CA 94305 – name: 1 Cancer Biology Division, Department of Radiation Oncology, Washington University School of Medicine, Saint Louis, MO 63108 – name: 4 Research Biotechnology Business Unit, Sigma-Aldrich Corporation, St. Louis, MO 63103 – name: 2 State Key Laboratory of Oral Diseases, Sichuan University, Chengdu 610041, China – name: 3 Department of Radiation Oncology, UT Southwestern, Dallas, TX 75390 |
Author_xml | – sequence: 1 givenname: Chong-kui surname: Sun fullname: Sun, Chong-kui organization: Cancer Biology Division, Department of Radiation Oncology, Washington University School of Medicine, Saint Louis, MO 63108 – sequence: 2 givenname: Fan surname: Zhang fullname: Zhang, Fan – sequence: 3 givenname: Tao surname: Xiang fullname: Xiang, Tao – sequence: 4 givenname: Qianming surname: Chen fullname: Chen, Qianming – sequence: 5 givenname: Tej K surname: Pandita fullname: Pandita, Tej K – sequence: 6 givenname: Yuping surname: Huang fullname: Huang, Yuping – sequence: 7 givenname: Mickey C T surname: Hu fullname: Hu, Mickey C T – sequence: 8 givenname: Qin surname: Yang fullname: Yang, Qin |
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SubjectTerms | Animals Antineoplastic Agents - pharmacology Breast Neoplasms - genetics Breast Neoplasms - metabolism Cell Line, Tumor Drug Resistance, Neoplasm - physiology Female Fluorescent Antibody Technique Gene Knock-In Techniques Humans Immunohistochemistry Mice Phosphorylation Phthalazines - pharmacology Piperazines - pharmacology Poly(ADP-ribose) Polymerase Inhibitors Research Paper Ribosomal Protein S6 - metabolism Sirolimus - pharmacology Ubiquitin-Protein Ligases - deficiency Xenograft Model Antitumor Assays |
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Title | Phosphorylation of ribosomal protein S6 confers PARP inhibitor resistance in BRCA1-deficient cancers |
URI | https://www.ncbi.nlm.nih.gov/pubmed/24831086 https://search.proquest.com/docview/1535627360 https://pubmed.ncbi.nlm.nih.gov/PMC4102816 |
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