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.

项目总结