# The inhibition of de novo purine synthesis increases LAMP2 expression to preserve cell viability

## TL;DR

Cancer cells increase LAMP2 to survive when their purine synthesis is blocked, which could help predict resistance to certain drugs.

## Contribution

Identifies LAMP2 upregulation as an adaptive response to purine synthesis inhibition in cancer cells.

## Key findings

- LAMP2 expression is a determinant of resistance to purine synthesis inhibitors.
- Purine synthesis inhibitors increase LAMP2 through ROS- and transcriptional-dependent mechanisms.
- High LAMP2 levels may indicate intrinsic resistance to these drugs in tumors.

## Abstract

Cancer cells rewire their metabolism to sustain the high proliferative rate. Metabolism is therefore a common vulnerability of cancer cells, successfully exploited for therapeutic purposes. Intrinsic tumor characteristics and adaptive responses of cancer cells can however reduce the short and long-term efficacy of such a strategy. Understanding the determinants of therapy response and the mechanisms of chemoresistance is crucial to maximize therapy efficacy. In cancer, lysosomes undergo massive changes in their localization, size, and composition that support tumor progression. Additionally, lysosomes are one of the crucial drivers of chemoresistance via the drug sequestration or by facilitating adaptations to stress conditions. In the last decades, several reports have shown that lysosomal membrane proteins, such as the lysosome-associated membrane proteins 1 and 2 (LAMP1 and LAMP2), are deregulated in different cancer types and their expression has been correlated to drug efficacy. We performed an in silico gene essentiality and drug sensitivity screenings, revealing that LAMP2 expression is one of the determinants of resistance to inhibitors of de novo purine synthesis. In vitro experiments confirmed the in silico data and also showed that purine synthesis inhibitors trigger a ROS- and transcriptional-dependent increase of LAMP2. Our results identify the upregulation of LAMP2 expression as an adaptive response to purine synthesis inhibition to preserve cell viability and, in those tumors showing high LAMP2 levels, could also be an indicator of intrinsic resistance to these drugs that may be taken into consideration during the selection of the most appropriate therapy.