# Functional Networks for Persister Cell Sensitivities

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2021 · $505,756

## Abstract

Project Summary
In this proposal we aim to characterize and identify mechanisms for the persister cell state. Specifically,
we have found that cancer persister cells are specifically and potently sensitive to ferroptosis, a newly
discovered non-apoptotic cell death program which involves toxic buildup of lipid hydroperoxides.
Ferroptotic death can be induced by chemical or genetic inhibition of GPX4, the primary human
antioxidant which scavenges lipid peroxides. We have found that drug naïve parental cancer cells and
nontransformed human epithelial cells are insensitive to ferroptosis and propose to elucidate the
molecular basis for persister cell sensitivity to ferroptosis. This will be accomplished via cellular and
molecular approaches including high throughput genetic interaction screens.
In Aim 1, we plan to evaluate the generality of our observations in breast cancer persister cells in other
cancer types including melanoma, ovarian and lung cancer. We will determine mechanisms for why
persisters are potently and specifically sensitive to ferroptosis, while their parental cancer cells are
insensitive. This will be accomplished by measurement of anti- and pro-oxidant cellular metabolites
and cofactors (e.g. glutathione and iron), differentially peroxidated lipids upon GPX4 inhibition, ROS
signaling pathways and other mechanistic analyses. These experiments will provide a framework for
genetic interaction studies described in Aim 3. In Aim 2, we will also establish the role for GPX4 in
persister cell survival and acquired drug resistance in cancer cell xenografts, PDXs and syngeneic
immunocompetent mouse models of breast cancer and melanoma by inducing ferroptosis in persisters
in vivo. Preventing tumor recurrence by inducing ferroptosis in persister cells in vivo will be a significant
result to promote further work towards clinical intervention targeting GPX4.
We will also focus on our efforts to identify the genetic interactions behind the persister state and its
sensitivity to ferroptosis. In Aim 3 we will build on our existing efforts to develop a platform for
conducting persister gene interaction maps (EMAPs). This is will help us identify the relationship
between our screen hits, with the hope of identifying synergies among the genes and small molecules.
In addition it may help us discover new synergistic interactions with druggable genes. We have already
accomplished a pilot level EMAP analysis to establish feasibility, and here we propose to expand the
scope to the whole genome. The mechanisms underlying cancer persister cells have not been
thoroughly explored and this proposal will identify genes and disease relevance. Our accomplishments
will yield the first persister cell state genetic interaction map and pave the way to identify polytherapies
for translation to the clinic.

## Key facts

- **NIH application ID:** 10226239
- **Project number:** 5R01CA212767-05
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** MICHAEL T MCMANUS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $505,756
- **Award type:** 5
- **Project period:** 2017-08-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10226239

## Citation

> US National Institutes of Health, RePORTER application 10226239, Functional Networks for Persister Cell Sensitivities (5R01CA212767-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10226239. Licensed CC0.

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