By ecancer reporter Janet Fricker

Experimental restoration of the p53 tumour suppressor pathway in mouse models of lung cancer resulted in significant cell loss in malignant adenocarcinomas, but not in adenomas, reports a US study published in Nature.

Tumorigenesis is a multistep process that arises from the sequential accumulation of mutations in key oncogene and tumour suppressor pathways. An approach to personalised cancer therapy is currently under development based on targeting inactivation of tumour suppressors. Previous studies have suggested that some types of cancer are dependent upon sustained inactivation of the p53 tumour suppressor pathway (also known as Trp53) as tumours can undergo rapid and sometimes complete regression once p53 is restored.

In the current study to evaluate the therapeutic potential of p53 reactivation, David Feldser and colleagues from the Koch Institute for Integrative Cancer Research (Cambridge, Massachusetts, USA,) analysed the effect of p 53 restoration in mouse models of Kras driven lung cancer at different time points in tumour progression. P 53 restoration was achieved by delivering tamoxifen intraperitoneally to the mice twice weekly, while tumour volume was assessed with microcomputed tomography and tumour areas from histological analysis.

Results showed that the response of individual tumours was variable; indicating that only a subset of tumours was sensitive to p53 restoration. Upon p53 restoration adenocarcinomas, but not adenomas displayed features of cellular senescence. Further investigations revealed that Arf (a product of the Cdkn2a locus) was specifically expressed in adenocarcinomas, but not adenomas and was responsible for sensitising the tumours to p53 restoration. The point was demonstrated by an additional study showing that inhibition of Arf allowed adneocarcinomas to continue to proliferate following the addition of tamoxifen.

"These data indicate that Arf is required for p53 induced cell cycle arrest in this system," wrote the authors, adding that their study raised that possibility that reactivation of the defective p53 pathway could have important future implications for anti-cancer therapies.

Reference

DM Feldser, KK Kostova, MW Winslow, et al Stage-specific sensitivity to p53 restoration during lung cancer progression. Nature Doi: 10.1038/nature 09535