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New insights about wild-type p53 restoration across mutant landscapes and genotype specific sensitivity to Statins in Lung Cancers.

last modified Aug 10, 2017 09:12 PM

Lung cancer is the leading cause of cancer related death worldwide due to its high incidence rates and limited effectiveness of available therapies. Approximately half of lung adenocarcinomas, the most common type of lung cancer, harbor mutations in a gene called TP53 (p53). p53, also known as 'the guardian of the genome', is a key player in the body’s in built defence mechanism against the development of cancer. However, due to its prominent tumour suppressive role, p53 is very frequently inactivated in cancer through mutations, being the single most commonly mutated gene in human cancers. As a consequence, p53 is also one of the most appealing cancer therapy targets.

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Therapeutic vulnerabilities of lung tumours with distinct p53 mutations
However, as mutant p53 proteins cannot currently be targeted in the clinic, alternative targeting strategies aimed at these tumours are required. To identify mutant p53-dependent therapeutic vulnerabilities in lung tumours, Dr Carla Martins and her colleagues, at the Unit studied the transcriptional, metabolic and cellular characteristics of lung tumour models harboring distinct p53 deficiencies, namely complete loss of p53 (Null); mutations that cause loss of p53 contact with DNA and mutations that alter the correct conformation of the protein. Their work reveals that lung tumours with distinct p53 deficiencies have both common and distinct therapeutic vulnerabilities, and some of these may potentially be exploited with available therapies. On the one hand, this study shows that p53 restoration therapy, which is currently under development, is equally effective in p53-null and mutant lung tumours, demonstrating the potential of this therapeutic approach even when p53 mutations are present. On the other hand, the authors found that each p53 deficiency drove unique gene expression signatures that can in turn lead to mutation-specific vulnerabilities. In particular, they found that tumours with p53 contact mutations were sensitive to treatment with the cholesterol lowering drug simvastatin, a type of Statin, but this sensitivity was not observed in the other two p53 deficient tumour cohorts. Importantly, the authors identified a similar p53-mutation type specific gene expression signature in human lung tumors. This raises the exciting possibility that these specific subsets of lung cancer patients may profit from statin repurposing as a cancer therapy.

The study entitled Lung tumors with distinct p53 mutations respond similarly to p53 targeted therapy but exhibit genotype-specific statin sensitivity has been published in Genes and Development on the 9th of August, 2017.

Further information on research carried out by the Martins group can be found here.