# Elucidating connections between anastasis and cancer drug resistance

> **NIH NIH R21** · JOHNS HOPKINS UNIVERSITY · 2020 · $411,118

## Abstract

Project Summary
Activating programmed cell death such as apoptosis is one of the most important therapeutic strategies
for cancer therapy. Many cancers undergo dramatic initial responses to such therapy. However, cancer
relapse with the development of drug resistance is a major problem in the clinical management of most
types of cancer, leading to treatment failure. The classical view of cell death has long assumed that,
once initiated, the apoptotic dying process is irreversible. However, we discovered that dying cancer
cells and primary cells can reverse the apoptotic process even at late execution stages, and named this
cell recovery mechanism Anastasis (Greek for “rising to life”). The discovery of anastasis suggests an
unexpected tactic that cancer cells could use to escape cell death-inducing cancer therapy. Central to
this proposal, we have demonstrated that some cells acquired permanent genetic changes during
anastasis and undergo oncogenic transformation at a higher frequency than controls. Moreover,
anastatic cells display an increased resistance to apoptotic stimuli such as anticancer drugs. These
observations lead to an intriguing question: Can anastasis contribute to the development of drug
resistance in recurrent tumors? If so, anastasis would be a potential and novel therapeutic target for
suppressing cancer progression and recurrence. Since mutations contribute to the development of
resistance, we propose that cancer cell survival by anastasis occurring at the interval between cycles of
anticancer therapy could allow apoptosis-caused DNA damage to be perpetuated and lead to
mutagenesis, progression, and evolution of drug resistance in recurrent cancers. In Specific Aim 1, we
propose to test for and identify such mutations if they occur, and determine whether mutational hotspots
exist in anastatic cells. We will then compare any mutations identified with the known mutational
signatures that have been mapped in recurrent clinical tumors. This will directly test for connections
between anastasis and mutagenesis in cancer cells. In Specific Aim 2, we propose to compare the
sensitivity of anastatic cancer cells to different cell death inducers. Anastatic cells that have recovered
from repeated inductions of apoptosis often develop resistance to the same cell death stimulus. However,
it is not known whether these anastatic cells might also be resistant to other cell death inducers. We will
test for this possibility by determining whether anastasis increases resistance of cancer cells to higher
doses of the same inducer, and may also result in “cross-resistance” to other pathways of cell death, e.g.,
autophagy, ferroptosis, and necroptosis. Overall, these studies seek to elucidate connections between
anastasis and development of drug resistance in cancer cells that can be targeted and useful in new
approaches to anticancer therapy.

## Key facts

- **NIH application ID:** 10056879
- **Project number:** 1R21CA249362-01A1
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Ho Lam Tang
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $411,118
- **Award type:** 1
- **Project period:** 2020-08-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10056879

## Citation

> US National Institutes of Health, RePORTER application 10056879, Elucidating connections between anastasis and cancer drug resistance (1R21CA249362-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10056879. Licensed CC0.

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