Evolution of cancer cell phylogenies and phenotypes in breast cancer resistance

摘要

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.