# Overcoming Cancer Resistance Mediated by the Human MDR1 Transporter

> **NIH NIH R01** · UNIVERSITY OF GEORGIA · 2021 · $350,605

## Abstract

Anti-cancer drug-resistant tumors represent a major impediment to effective cancer therapy. One of
the main pathways of cancer resistance is through the human multidrug resistance 1 (MDR1) trans-
porter, which effluxes a relatively broad range of anti-cancer drugs and has been identified in ~50% of
cancerous tumors. Despite findings from numerous studies, anti-cancer drug-transporter interactions
and their molecular transport mechanisms are currently not well understood. To broaden our under-
standing of anti-cancer drug transport by MDR1, there is a critical need to define the molecular and
structural basis of anti-cancer drug transport. Our overall objective in the proposed studies is to define
the molecular mechanisms of anti-cancer drug transport, to identify anti-cancer drug functional groups
that interact with the transporter and to pinpoint the anti-cancer drug binding sites on the MDR1
transporter. Based on the known X-ray crystal structure of the mouse mdr3 transporter, the central
hypothesis is that the anti-cancer drug transport rate by human MDR1 is controlled by multiple drugs
binding in close proximity to the extracellular side of the transporter (near Y953). From this central
hypothesis, two specific aims are proposed: The first specific aim is to define the mechanism of anti-
cancer drug transport by MDR1 and to test the hypothesis that the anti-cancer drug transport rate is
directly related to the number of anti-cancer drug binding sites. The second specific aim is to deter-
mine the anti-cancer drug bound MDR1 conformations using atomic force microscopy (AFM) and to
pinpoint the locations of anti-cancer drugs on MDR1 by NMR. These investigations have been de-
signed to test the hypothesis that anti-cancer drugs with higher transport rates have binding sites
relatively close to the extracellular side of the transporter. Ultimately, the successful completion of
these studies will lead to the identification of specific anti-cancer drug properties that lead to MDR1-
mediated transport. This information will allow us to design of novel fourth generation MDR1 trans-
porter inhibitors and to make rational modifications of candidate and commercially available anti-
cancer drugs to minimize MDR1-mediated efflux. Without the new knowledge from the completion of
this research, effective strategies for rationally designing drugs that can effectively overcome MDR1-
mediated cancer resistance are likely to remain limited and MDR1-mediated drug resistance will re-
main a leading cause of cancer resistance and mortality.

## Key facts

- **NIH application ID:** 10238124
- **Project number:** 5R01CA204846-05
- **Recipient organization:** UNIVERSITY OF GEORGIA
- **Principal Investigator:** Arthur G Roberts
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $350,605
- **Award type:** 5
- **Project period:** 2017-08-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10238124

## Citation

> US National Institutes of Health, RePORTER application 10238124, Overcoming Cancer Resistance Mediated by the Human MDR1 Transporter (5R01CA204846-05). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10238124. Licensed CC0.

---

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