Evolution of cancer cell phylogenies and phenotypes in breast cancer resistance

乳腺癌耐药中癌细胞系统发育和表型的进化

• 批准号: 10599731
• 负责人: ANDREA Hope BILD
• 金额: $ 9.33万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10599731
• 关键词: Attenuated; Biopsy; Breast Cancer Patient; Bypass; CDK4 gene; Cell Cycle; Cell Cycle Progression; Cell Proliferation; Cell division; Cells; Clinical; Clinical Trials; Combined Modality Therapy; DNA Sequence Alteration; ESR1 gene; Endocrine; Estrogen Receptors; Estrogen receptor positive; Estrogens; Evolution; FDA approved; FGFR2 gene; Genes; Genetic; Genotype; Grant; Hormones; Hyperactivity; Letrozole; Link; MAP Kinase Gene; MAPK8 gene; Metastatic breast cancer; Mitogen-Activated Protein Kinase Kinases; Modeling; Mutation; Outcome; Parents; Pathway interactions; Patient-Focused Outcomes; Patients; Phenotype; Phylogenetic Analysis; Phylogeny; Preoperative Endocrine Therapy; Protein Tyrosine Kinase; Proteins; Receptor Protein-Tyrosine Kinases; Resistance; Resistance development; Role; Sampling; Signal Transduction; Testing; Treatment Protocols; Treatment outcome; Trees; United States National Institutes of Health; Up-Regulation; base; cancer cell; cancer type; exome; hormone therapy; improved; inhibitor; interpatient variability; malignant breast neoplasm; receptor; receptor upregulation; resistance mechanism; transcriptomics; treatment response; treatment strategy; tumor; tumor growth

Abstract Cyclin-dependent kinases 4/6 (CDK4/6), critical components in cell division decisions, are hyperactive in different cancer types. To control over proliferation of cancer cells, a recently FDA-approved class of CDK inhibitors emerged. Compounds targeting CDK4/6 as Ribociclib are clinically proven to reduce tumor growth and extend patient survival in metastatic breast cancer. However, resistance mechanisms to CDK4/6 inhibitors have been identified including the upregulation of receptor tyrosine kinase (RTK) and MAPK pathway activation. We previously analyzed serially collected patient tumor samples from day 0, 14, and 180 of treatment with either endocrine therapy alone or in combination with ribociclib. Our results identified different receptor tyrosine kinases upregulation and signaling through MAPK pathways as resistance mechanisms to combination therapy. However, the role of an underlying genetic mutations of RTKs and MAPK-induced resistance is lacking. In aim 1, I will increase the sensitivity of detecting subclones influencing phenotypic resistance through RTK/MAPK signaling by constructing RTK/MAPK-specific phylogenetic trees to dissect the subclonal evolution. I will also construct RTK/MAPK non-specific phylogenies to detect indirect effect of genetic subclones on RTK/MAPK resistant phenotypes. Using generalized linear mixed model, aim 2 will test for the association between resistant RTK/MAPK phenotypes and RTK/MAPK-specific and non-specific subclones, treatment regimen, and patient outcomes. This proposal will not only explain the role of genotype in RTK/MAPK resistance but will also link the phenotype to treatment regimen and clinical outcomes over the course of therapy. Understanding the mechanisms by which genotype and phenotype interaction influence resistance to CDK4/6 inhibition can influence treatment strategies and improve patient outcomes.

抽象的 细胞周期蛋白依赖性激酶4/6（CDK4/6），细胞分裂决策的关键成分，在不同的 癌症类型。为了控制癌细胞的增殖，最近FDA批准的CDK抑制剂类 出现了。在临床上证明了靶向CDK4/6作为Ribociclib的化合物可减少肿瘤生长并延伸 患者在转移性乳腺癌中生存。但是，对CDK4/6抑制剂的抗性机制已经 鉴定出包括受体酪氨酸激酶（RTK）和MAPK途径激活的上调。我们 先前从第0、14和180天，以前分析了连续收集的患者肿瘤样本 单独或与Ribociclib结合内分泌疗法。我们的结果确定了不同的受体酪氨酸激酶 通过MAPK途径上调和信号传导，作为联合治疗的抗性机制。 但是，缺乏RTK和MAPK诱导的抗性的基本基因突变的作用。目标 1，我将增加检测通过RTK/MAPK影响表型抗性的亚克隆的灵敏度 通过构建RTK/MAPK特异性系统发育树来剖析亚克隆进化来传导。我也会 构建RTK/MAPK非特异性系统发育，以检测遗传亚克隆对RTK/MAPK的间接影响 抗性表型。使用广义线性混合模型，AIM 2将测试抗性之间的关联 RTK/MAPK表型以及RTK/MAPK特异性和非特异性亚克隆，治疗方案和患者 结果。该提案不仅可以解释基因型在RTK/MAPK抗性中的作用，而且还将联系起来 治疗过程中治疗方案和临床结果的表型。了解 基因型和表型相互作用影响CDK4/6抑制的机制可以 影响治疗策略并改善患者的预后。