Evolution of cancer cell phylogenies and phenotypes in breast cancer resistance

摘要 细胞周期蛋白依赖性激酶4/6（CDK 4/6）是细胞分裂决定中的关键组分，在不同的细胞中过度活跃。 癌症类型。为了控制癌细胞的增殖，最近FDA批准的一类CDK抑制剂 涌现靶向CDK 4/6的化合物如Ribociclib经临床证明可减少肿瘤生长并延长 转移性乳腺癌患者的生存率。然而，对CDK 4/6抑制剂的耐药机制已经被证实。 包括受体酪氨酸激酶（RTK）的上调和MAPK途径的激活。我们 先前分析的连续收集的患者肿瘤样品来自用以下任一种治疗的第0、14和180天： 内分泌治疗单独或与ribociclib联合。我们的结果鉴定了不同的受体酪氨酸激酶 通过MAPK途径的上调和信号传导作为对组合疗法的抗性机制。 然而，RTKs和MAPK诱导的抗性的潜在基因突变的作用是缺乏的。在aim中 1、提高了RTK/MAPK检测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。我也会 构建RTK/MAPK非特异性基因组，检测基因亚克隆对RTK/MAPK的间接影响 抗性表型利用广义线性混合模型，aim 2将检验抗性与 RTK/MAPK表型和RTK/MAPK特异性和非特异性亚克隆、治疗方案和患者 结果。这一建议不仅将解释基因型在RTK/MAPK抗性中的作用，而且还将与基因型之间的关系联系起来。 表型与治疗方案和治疗过程中的临床结果的关系。了解 基因型和表型相互作用影响对CDK 4/6抑制的抗性的机制可以 影响治疗策略并改善患者预后。

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.