Mechanistic insights into Variants of Uncertain Significance (VUS) using novel EGFR variants as a paradigm

使用新型 EGFR 变体作为范例对意义不确定的变体 (VUS) 进行机制洞察

• 批准号: 10379353
• 负责人: Christine M. Lovly
• 金额: $ 31.96万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-19 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10379353
• 关键词: Biochemical; Biological; Biological Assay; Biology; C-terminal; Cancer Patient; Cells; Chimeric Proteins; Chromosomal translocation; Clinic; Clinical; Computer Models; DNA Sequence Alteration; Data; Development; Dimerization; Disease; Doctor of Philosophy; ERBB2 gene; ERBB3 gene; Engineering; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; ErbB4 gene; Exons; FDA approved; Family; Family member; Future; Genomics; Genotype; Goals; Heterodimerization; Homodimerization; Human; Lung Adenocarcinoma; Lung Neoplasms; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Methods; Molecular; Mutate; Mutation; Nucleic Acid Regulatory Sequences; Oncogenic; Patient Care; Patients; Phenotype; Phosphorylation; Phosphotransferases; Physicians; Principal Investigator; Proteins; Receptor Activation; Recurrence; Reporting; Research; Research Personnel; Role; Signal Transduction; Single Nucleotide Polymorphism; Somatic Mutation; Structural Models; Techniques; Test Result; Testing; Therapeutic Agents; Translating; Transmembrane Domain; Variant; Work; actionable mutation; base; cancer therapy; cancer type; clinical diagnostics; clinical practice; clinically significant; diagnostic assay; diagnostic tool; dimer; drug development; drug sensitivity; experimental study; gene panel; genetic variant; in silico; in vivo; inhibitor; innovation; insight; multidisciplinary; next generation sequencing; novel; novel therapeutic intervention; polymerization; precision medicine; prospective; protein structure; receptor; standard of care; structural biology; targeted agent; therapeutic target; tool; tumor; tumorigenesis; variant of unknown significance

Mechanistic insights into Variants of Uncertain Significance (VUS) using novel EGFR variants as a paradigm Investigators: Christine M. Lovly, MD, PhD and Jens Meiler, PhD The prospective identification and rational therapeutic targeting of tumor genomic alterations has revolutionized the care of patients with lung cancer and is now the accepted standard of care for patients with this disease and with other tumor types. With the advent of sophisticated tumor genotyping, the discovery of novel genetic variants is accelerating. In order to realize the promise of precision medicine, there is an urgent need to define the actionability of these variants to select targeted inhibitors. The objective of this proposal is to develop a novel, data-driven paradigm for characterizing genomic Variants of Uncertain Significance (VUS) and generating actionable hypotheses about their functions. For this purpose, we propose an innovative `Personalized Structural Biology' approach. The central hypothesis of this paradigm is that VUS can be best understood by placing the mutation into the context of protein structures and inferring from the structural consequences of the mutation on function, phenotype, and drug sensitivity. By analyzing the tumors of patients with lung cancer, we have identified three EGFR genomic alterations that have not previously been reported: 1) EGFR exon 18-25 Kinase Domain Duplication, 2) EGFR- RAD51 fusions, and 3) EGFR transmembrane domain mutations. Importantly, each of these EGFR variants was reported as a VUS on clinical genotyping reports because there were no data regarding the sensitivity of the mutated proteins to EGFR inhibitors now used in clinical practice. We sought to study these EGFR VUS in an effort to understand on a fundamental mechanistic level how they activate the EGF receptor to promote oncogenesis. We will integrate structural and computational modeling with various biochemical, molecular, cell based, and in vivo approaches to investigate the functional effects of these three distinct alterations. Through these studies, we expect to define previously unrecognized mechanisms of oncogenesis in lung cancer defined by these novel and recurrently detected EGFR variants. Importantly, understanding the structural and functional consequences of these EGFR variants is expected to provide novel insights into ErbB receptor biology and reveal new uses for FDA approved agents in lung cancer and many other tumor types which harbor ErbB (EGFR/HER2/HER3/HER4) alterations. Furthermore, a key deliverable of the proposed studies is the development of an innovative, integrated in silico pipeline that is applicable to VUS in any type of cancer, which we will make freely available via RosettaCommons (www.rosettacommons.org). Thereby, the impact of the proposed research will go beyond that of the three EGFR variants discussed in this proposal. With the recent FDA approval of NGS-based tumor testing, the problem of VUS will continue to grow as these large (>300) gene panel clinical diagnostic assays are reaching higher volumes of patients. Therefore, it is imperative the field generate and systematically integrate such `personalized structural biology' methods to understand the functional significance of VUS in order to best serve all cancer patients.

利用新的EGFR变异作为不确定意义变异（VUS）的机制见解