Last Updated: 11/05/2023
Mechanism of resistance to lysosomotropic treatments: inhibition of autophagy and metabolic adaptations – LYSORES
Objectives
Mainly dedicated to sunitinib, the standard care of clear cell Renal Cell Carcinoma (ccRCC), the project work will be extended to lysosomotropic drugs such as chloroquine (anti-malaria) or azithromycin (antibiotic, asthma).
The objectives of this project are: i) To detect the lysosomotropic potential of any drugs; and ii) To understand the consequences of lysosome sequestration of drugs on metabolomic adaptations.
The physicochemical properties of drugs can lead to a therapeutic failure. Physicochemical properties can predictably influence intracellular distribution of a drug, an important consideration for its efficacy. In particular, drugs with LogP>2 and pKa>6 can be trapped in acidic intracellular compartments such as lysosomes away from their targets. Their protonation at acidic pH causes their sequestration and subsequent limitations of drug efficacy. These drugs are qualified as lysosomotropic. It was demonstrated that lysosomal sequestration results in an increase of the lysosome pH, which inhibits lysosomal proteases and leads to an incomplete autophagic process. The physio-pathological consequences of sequestration in lysosomes and the adaptation to autophagic defects need better understanding. The recent results reveal that lysosomotropic-dependent inhibition of autophagy results in the activation of the serine biosynthetic pathway leading to a metabolic adaptation and sustained proliferation. The comprehensive investigations of metabolic alterations in response to lysosomotropic drugs resulting in acquired resistance have never been conducted.
Mar 2022 — Mar 2025
$347,108
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