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(CDK4/6)是细胞分裂决定的关键成分，在不同的细胞周期中处于过度活跃的状态。 癌症类型。为了控制癌细胞的过度增殖，最近FDA批准的一类CDK抑制剂 出现了。以CDK4/6为靶点的化合物被临床证明可以减少肿瘤的生长和扩展 转移性乳腺癌患者的存活率。然而，CDK4/6抑制剂的耐药机制一直是 发现包括受体酪氨酸激酶(RTK)的上调和MAPK通路的激活。我们 先前分析了连续收集的患者肿瘤样本，从治疗的第0、14和180天开始 内分泌治疗单独或与核环素联合应用。我们的结果鉴定出不同的受体酪氨酸激酶 MAPK通路上调和信号转导作为联合治疗的耐药机制。 然而，RTKs的潜在基因突变和MAPK诱导的耐药性的作用尚不清楚。在AIM 1、通过RTK/MAPK提高检测影响表型抗性的亚克隆的敏感性 通过构建RTK/MAPK特异的系统发育树来剖析亚克隆进化。我也会 构建RTK/MAPK非特异性系统树以检测遗传亚克隆对RTK/MAPK的间接影响 耐药表型。使用广义线性混合模型，AIM 2将检验抗性之间的关联 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在RTK/MAPK耐药中的作用，还将把 治疗方案的表型和治疗过程中的临床结果。了解 基因型和表型互作影响对CDK4/6抑制抗性的机制 影响治疗策略，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.