# Melanoma subpopulations that rapidly escape MAPK pathway inhibition incur DNA damage and rely on stress signalling

## TL;DR

Some melanoma cells quickly escape BRAF inhibitor treatment through non-genetic means, causing DNA damage and relying on stress signals to survive.

## Contribution

The study reveals non-genetic mechanisms enabling rapid drug escape in melanoma cells under BRAF inhibitor treatment.

## Key findings

- A subset of melanoma cells escapes BRAF inhibition within three days via non-genetic mechanisms.
- Escaped cells rely on ATF4 stress signaling and experience DNA replication defects.
- These cells out-proliferate others over time despite DNA damage.

## Abstract

Despite the increasing number of effective anti-cancer therapies, successful treatment is limited by the development of drug resistance. While the contribution of genetic factors to drug resistance is undeniable, little is known about how drug-sensitive cells first evade drug action to proliferate in drug. Here we track the responses of thousands of single melanoma cells to BRAF inhibitors and show that a subset of cells escapes drug via non-genetic mechanisms within the first three days of treatment. Cells that escape drug rely on ATF4 stress signalling to cycle periodically in drug, experience DNA replication defects leading to DNA damage, and yet out-proliferate other cells over extended treatment. Together, our work reveals just how rapidly melanoma cells can adapt to drug treatment, generating a mutagenesis-prone subpopulation that expands over time.

BRAF inhibitors are used to treat late-stage melanoma patients harbouring BRAF mutations. Here the authors track the responses of single melanoma cells to BRAF inhibitors and show that a subset of cells rapidly escapes drug via non-genetic mechanisms and incurs DNA damage.