Seeking synergy in p53 transcriptional activation for cancer therapy.

Targeting the p53-MDM2 pathway is regarded as a viable therapeutic strategy and is supported by several preclinical mouse models which show that the restoration of p53 activity leads to tumor regression in vivo. Given that a large proportion of cancers, including hematological malignancies, retain the expression of the wildtype p53 allele, reactivating wildtype p53 in these cancers could lead to selective apoptosis and is regarded as a potential therapeutic strategy. The exploration of inhibitors and peptides targeting the p53-MDM2 pathway led to the discoveries of specific small molecule inhibitors that disrupt the MDM2-mediated inhibition of p53 transcriptional activity and protein stability. Nutlin is one of the specific small molecule that is well tolerated in vivo in mice but has been used in combinations with conventional chemotherapy and radiotherapy, as well as molecularly targeted drugs to further increase its specificity and potency in vivo. We attempt to identify pathways or new targets which when inhibited may synergize with nutlin in its activation of p53 transcriptional activity. Our previous results show that CDK inhibition synergizes with nutlin in p53 activation and p53-dependent apoptosis, converting a cell cycle arrest response to apoptosis. Here, using a siRNA screen against 726 human kinases, we identified several pathways, including the MAP kinase pathway, the sphingosine kinase pathway, and the CDK pathway which may have crosstalk with the p53 pathway. Selective inhibition of these pathways may synergize with nutlin in the induction of p53 transcriptional activity.