Deciphering the mechanisms of drug resistance associated with ALDH1 enzymes – DECIPHER

Overcoming drug resistance in cancer is a major challenge because of the complex networks of genetic and epigenetic adaptation that enable cancer cells to persist despite treatment. These networks modify the cell signalling pathways and metabolic dependencies of the cells, making them resistant to treatment. Identifying vulnerabilities in these networks is essential for developing more effective therapies.
The enzymes aldehyde dehydrogenase 1 (ALDH1) are a promising target in certain treatment-resistant advanced cancers, such as acute myeloid leukaemia, T-acute lymphoblastic leukaemia, triple-negative breast cancer and lung cancer. ALDH1 plays a key role in oxidative and lipid metabolism, detoxification of chemotherapeutic agents, and is highly expressed in cancer stem cells, which are often responsible for resistance. However, the lack of specific inhibitors and a limited understanding of the mechanisms underlying ALDH1-mediated resistance have delayed therapeutic advances.
Totackle this challenge, the Theories and Approaches to Genomic Complexity Laboratory (TAGC), affiliated to INSERM and the University of Aix-Marseille, is collaborating with Advanced BioDesign (ABD), a company specializing in ALDH1 inhibitors. Together, they propose to create the LabCom DECIPHER, which aims to combine genetic and epigenetic research with the analysis of signaling pathways and pharmacology to develop innovative therapies for drug-resistant cancers.
DECIPHER's strategy is based on four main axes:
1. Study of genetic and epigenetic mechanisms: Identification of molecular networks, in particular those linked to ALDH1, that contribute to treatment resistance.
2. CRISPR/Cas9 functional genomics: This technology will make it possible to identify the key genes responsible for resistance through large-scale screening, opening up new prospects for therapeutic targets.
3. Analysis of cell signalling pathways: Studying the adaptive signalling networks of cancer cells will enable us to understand how these networks support their survival and how they can be disrupted to make cells vulnerable to treatment.
4. Pharmacological studies: pharmacological screening will be carried out to explore drug combinations aimed at targeting resistant cells, with a particular focus on ALDH1 inhibitors.
The multidisciplinary DECIPHER LabCom aims to identify the weaknesses of treatment-resistant cancer cells, in particular their new metabolic dependencies. These discoveries could lead to the development of revolutionary therapies to treat resistant cancers, offering more effective and personalised solutions for patients.