Precision therapy in the p53 pathway
Session type: Poster / e-Poster / Silent Theatre session
Mutation in the Tp53 gene frequently occurs in various human cancers; yet, therapies against this large cohort of cancers are lacking. Targeting p53 deficiency, in particular, through exploiting the altered fitness of tumor cells harboring p53 mutations presents unique opportunities to target a broad spectrum of p53 mutations that are clinically prevalent, including hotspot missense and nonsense mutations. Despite the discoveries of various roles of p53 in diverse cellular functions, pharmacologic manipulation of these complex pathways for therapeutic benefit still remains challenging. We have taken a synthetic lethal approach to screen for selective sensitizers of tumor cells harboring p53 deficiency.
We developed a robust and sensitive fluorescence-based imaging assay to screen for new synthetic lethal interactions in the p53 pathway. Differentially labeled isogenic cells containing wildtype or p53 deletion were co-cultured and subjected to a Pharmakon library of 1600 FDA-approved compounds.
Through a HTS screen, we identified an FDA-approved anthelmintic that preferentially impaired the growth of p53-mutant cells, of both human and mouse origins. In addition to an extensive validation performed using cell line panels, we established cancer cell line and patient-derived xenografts (PDX), and demonstrated that loss or mutation of p53 led to increased tumor growth reduction following monotherapy with the anthelmintic. Metabolome profiling reveals unexpectedly that deficiency in p53 led to a preferential accumulation of a fatty acid that underlies a catastrophic mitochondrial-dependent cell death induced by the anthelmintic niclosamide. Deconvolution of the mechanism of drug action led us to uncover new roles of p53 in promoting cell survival by efficiently coupling the transcriptional activation of lipid oxygenation genes to counteract metabolic crisis induced by niclosamide.
We proposed a new paradigm for targeting p53 mutation/loss by exploiting their vulnerability to niclosamide-induced mitochondrial uncoupling (accepted in Nature Communications). Further implications of new findings will be discussed.