Precision therapy in the p53 pathway


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Chit Fang Cheok1,Luis Coronel2,Ramesh Kumar3,Bhagi Somalanka3,Raju Anandh1,Obed Aning4,Ping Yin Hor5,An Omer6,Yingswan Ho7,Chen Shuwen7,Shi Ya Mak7,Henry Yang8,Mani LAKSHMANAN4,Hideki Itoh9,Soo Yong Tan10,Timothy Lim11,Adele Wong11,Sung Hock Chew11,The Hung Huynh12,Boon Cher Goh13,Vinay Tergoankar4,Chin Yan Lim9
1Institute of Molecular and Cell Biology (IMCB), A*STAR,2p53Laboratory, A*STAR,3IFOM-p53Lab JRL,4Institute of Molecular and Cell Biology (IMCB),5IFOM-p53Lab, A*STAR,6Cancer Science Institut, NUS,7Bioprocessing Technology Institute, A*STAR,8Cancer Science Institute, NUS,9Institute of Medical Biology, A*STAR,10Department of Pathology, NUS,11KK Women’s and Children’s Hospital,12National Cancer Center Singapore,13National University Cancer Institute

Abstract

Background

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.

Method

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.

Results

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.

Conclusion

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.