# Epigenetic mechanisms of drug resistance in renal cell carcinoma

> **NIH NIH R01** · INDIANA UNIVERSITY INDIANAPOLIS · 2020 · $406,936

## Abstract

Receptor tyrosine kinase inhibitors (RTKIs) such as sunitinib, pazopanib and axitinib are effective treatments
for clear cell renal cell carcinoma (ccRCC) patients. However, resistance to RTKIs represents a major hurdle in
the clinical management of advanced ccRCC. Despite the clinical benefit, acquired resistance to RTKIs occurs
within 12 months in the first line setting. Our preliminary data suggest that the expression of the polycomb
protein enhancer of zeste homolog2 or EZH2, a histone methyltransferase, may be associated with sunitinib
resistance in patient-derived xenograft models (PDXs) and human RCC cell lines. Serendipitously, a reverse-
protein phase analysis of our PDX model chronically exposed to sunitinib showed a significant upregulation of
the androgen receptor (AR) expression following drug resistance. Interestingly, AR is expressed in RCC and a
cross-talk between EZH2 and AR has been proposed in prostate cancer. Our preliminary data also suggest
that the combination of sunitinib and either EZH2 or AR inhibitors has greater antitumor effect than single
agents both in vitro and in vivo.
The overall objective of this application is to determine the role of epigenetics in resistance mechanisms to
RTKIs in ccRCC, to assess the epigenomic signature associated with this resistance phenotype, and to
develop novel therapeutic strategies to induce epigenetic reprogramming and consequently overcome loss of
response to RTKIs. Our central hypothesis is that (acquired and/or innate) resistance to RTKIs may be caused
by reversible epigenetic changes and molecular characterization of the resistant phenotype will lead to the
identification of novel targets for therapeutic interventions. Taken together, we hypothesize that EZH2 and AR
may drive tumor adaption to RTKIs and loss of direct antitumor effect of these drugs in RCC
We will test our central hypothesis and, thereby, accomplish the objective of this application by pursuing the
following three specific aims: 1) To determine the role of EZH2 and AR in RTKIs resistance in ccRCC models;
2) To assess the impact of EZH2 and AR modulation on reversing RTKIs resistance in ccRCC models; 3) To
assess EZH2 and AR status in ccRCC patients and correlate it with response to RTKIs.
We expect that these studies will provide 1) a direction to improve RKTI therapy; 2) the epigenetic signature
associated with resistance to RTKIs; and 3) preliminary data for novel predictive biomarkers and targets
suitable for therapeutic intervention. Taken together, the results from these studies will provide useful
information that can be translated in the clinical setting and have an impact in the treatment of advanced
kidney cancer.

## Key facts

- **NIH application ID:** 9854899
- **Project number:** 5R01CA224342-03
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** Naomi B Haas
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $406,936
- **Award type:** 5
- **Project period:** 2018-02-01 → 2021-01-04

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9854899

## Citation

> US National Institutes of Health, RePORTER application 9854899, Epigenetic mechanisms of drug resistance in renal cell carcinoma (5R01CA224342-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9854899. Licensed CC0.

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