Novel Mechanisms of MED12-TGFbeta-mediated resistance to PARP Inhibitors in BRCA-deficient Cancer Cells

MED12-TGFbeta 介导的 BRCA 缺陷癌细胞对 PARP 抑制剂耐药的新机制

• 批准号: 10665588
• 负责人: Lindsey Marie Pale
• 金额: $ 3.44万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10665588
• 关键词: Address; Antineoplastic Agents; Architecture; Aspergillus Nuclease S1; BARD1 gene; BRCA deficient; BRCA1 gene; BRCA2 gene; Binding; Biological Assay; Breast Cancer Cell; Bromodeoxyuridine; Cancer Patient; Cells; Chemoresistance; Cisplatin; Clinic; Clustered Regularly Interspaced Short Palindromic Repeats; Complement; Complex; Cryoelectron Microscopy; DNA Damage; DNA Repair; DNA Repair Gene; DNA replication fork; Data; Development; Disease remission; Double Strand Break Repair; Drug resistance; Exposure to; Fiber; Gene Expression; Genetic Determinism; Genetic Screening; Genome Stability; Genomic Instability; Genomics; Goals; Hela Cells; Knock-out; Knowledge; Laboratories; Maintenance; Malignant Neoplasms; Malignant neoplasm of ovary; Mediating; Mediator; Medicine; Mentorship; Oncology; PALB2 gene; Pathway interactions; Patients; Peptides; Pharmaceutical Preparations; Phenotype; Poly(ADP-ribose) Polymerase Inhibitor; Publications; Publishing; Research; Resistance; Resources; Role; Sampling; Scientist; Signal Pathway; Single-Stranded DNA; Small Interfering RNA; Structure; Techniques; Testing; Therapeutic; Transforming Growth Factor beta; Work; anticancer research; cancer cell; clinically relevant; college; experience; genome-wide; graduate student; homologous recombination; hydroxyurea; inhibitor; leukemia; malignant breast neoplasm; mutant; novel; novel therapeutic intervention; particle; protein complex; protein expression; repaired; resistance mechanism; response; restoration; skills; therapy resistant

Project Summary This F31 application focuses on characterizing a novel resistance mechanism for PARP inhibitors. I am requesting support for developing a project which I have previously initiated and published on. This proposal addresses a fundamental gap in knowledge and could significantly impact cancer therapeutic strategies and cancer patient survival. Moreover, the resources this application would provide would greatly impact my development as a graduate student and independent scientist. This proposal would allow me the opportunity to be exposed to state-of-the-art laboratory techniques including genomic sequencing and cryo-EM. This would provide me with a complex mix of critical skills that will be important for my development into a well-rounded scientist, and for which are highly attainable due to the support and resources provided by my mentorship team and at Penn State College of Medicine. In this proposal, I focus on elucidating the mechanisms by which MED12 and TGFb mediate resistance to PARP inhibitors. I previously showed loss of MED12 confers resistance to PARP inhibitors in BRCA-deficient cells via activation of the TGFb pathway. This resistance was underscored by an increase in homologous recombination DNA repair efficiency and replication fork stability following TGFb pathway activation in BRCA-deficient cells. Here, I hope to expand on this research to further define the mechanism behind this chemoresistance, to reduce this gap in knowledge, and to gain experience and expertise in the rapidly growing field of structural oncology in cancer research. To investigate the role of MED12 and TGFb in chemoresistance further, I will explore three aims: 1) Investigate specific interactions between MED12 with the Mediator complex and TGFbR2 and the impact of these interactions on chemosensitivity in BRCA-deficient cells, 2) determine the role of ssDNA gap suppression in MED12-TGFb-mediated chemoresistance and genomic stabilization, and 3) investigate the impact of TGFb activation on the structure of mutant BRCA1 in patient-derived HCC1937 breast cancer cells. Achieving these aims will expand my knowledge in the field of DNA damage and repair and expose me to cutting-edge new techniques in the field of structural oncology. Thus, this work will advance my personal goals, and significantly impact the field by providing new information on chemosensitivity in patients harboring BRCA-mutant cancers.

项目摘要 该F31应用的重点是表征针对PARP抑制剂的新型抗性机制。我是 请求支持我以前启动和发布的项目。这个建议 解决知识的根本差距，可能会对癌症治疗策略产生重大影响，并 癌症患者的生存。此外，该应用程序将提供的资源将极大地影响我的 作为研究生和独立科学家的发展。该建议将使我有机会 接触到包括基因组测序和冷冻EM在内的最先进的实验室技术。这会 为我提供复杂的关键技能组合，这对于我发展到全面的发展非常重要 科学家，由于我的指导团队提供的支持和资源，这是高度实现的 并在宾夕法尼亚州立医学院。 在此提案中，我专注于阐明Med12和TGFB介导对PARP的机制 抑制剂。我先前显示Med12的丧失赋予了对BRCA缺陷细胞中PARP抑制剂的抗性 TGFB途径的激活。同源重组的增加，强调了这种电阻 在BRCA缺陷细胞中TGFB途径激活后，DNA修复效率和复制叉稳定性。 在这里，我希望对这项研究进行扩展，以进一步定义这种化学抗性的机制，以减少 知识的差距，并在结构肿瘤学领域的经验和专业知识中获得经验和专业知识 癌症研究。 为了进一步研究Med12和TGFB在化学耐药性中的作用，我将探讨三个目标：1）调查 Med12与介体复合物和TGFBR2之间的特定相互作用以及这些的影响 关于BRCA缺陷细胞中化学敏度的相互作用，2）确定ssDNA间隙抑制在 MED12-TGFB介导的化学耐药和基因组稳定，3）研究TGFB的影响 在患者衍生的HCC1937乳腺癌细胞中突变BRCA1结构的激活。实现这些 目标将扩大我在DNA损坏和维修领域的知识，并使我接触到最先进的新 结构肿瘤学领域的技术。因此，这项工作将促进我的个人目标，并显着 通过提供有关具有BRCA突变癌症患者的化学敏度的新信息来影响该领域。