# Evolution of cancer cell phylogenies and phenotypes in breast cancer resistance

> **NIH NIH U01** · BECKMAN RESEARCH INSTITUTE/CITY OF HOPE · 2022 · $93,333

## Abstract

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.

## Key facts

- **NIH application ID:** 10599731
- **Project number:** 3U01CA264620-02S2
- **Recipient organization:** BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
- **Principal Investigator:** ANDREA Hope BILD
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $93,333
- **Award type:** 3
- **Project period:** 2021-09-01 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10599731

## Citation

> US National Institutes of Health, RePORTER application 10599731, Evolution of cancer cell phylogenies and phenotypes in breast cancer resistance (3U01CA264620-02S2). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10599731. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*