IGF2: The Achilles' heel of p53‐deficiency?

Abstract

See related article in EMBO Molecular Medicine http://dx.doi.org/10.1002/emmm.201101105 There is growing evidence that inactivation of the p53 tumour suppressor pathway is required for full‐blown tumourigenesis (Levine, 1997). While half of human cancers harbour mutations or deletions of the p53 tumour suppressor locus, the remaining cancers employ alternative mechanisms to subvert the activity of wild‐type p53. This clinically relevant pathway has therefore logically become the target for the development of innovative avenues in cancer therapy. For instance, restoration of p53 function has been extensively pursued as a therapeutic modality in cancers in which p53 function is compromised although the TP53 locus remains intact (Brown et al, 2009). Such approach is, however, only applicable to tumours expressing wild‐type p53. Because alteration of p53 is so frequent in cancer, identification of synthetic lethal partners of p53 should lead to conceptually simple and attractive approaches to selective targeting of cancer cells (Kaelin, 2005). Inactivation of such a target would in theory be detrimental to virtually all cancer cells irrespective of the mechanisms that led to p53 inactivation. In the present issue, Haley and colleagues (Haley et al, 2012) provide evidence for a synthetic lethal interaction between the p53 and Igf2 pathways. IGF2 is a growth‐promoting hormone during gestation and commonly overexpressed in human cancer through re‐expression of the imprinted maternal allele by loss of imprinting (LOI). IGF‐2 exerts its effects by binding to the IGF‐1 receptor and activating both the PI3K‐AKT‐mTOR and RAS‐RAF‐MEK‐ERK downstream signalling pathways. Although previous in vitro studies highlighted several mechanistic pathway interactions between IGF2 and p53 signalling genetic evidence for such interactions was lacking. To search for such genetic links in vivo , Haley and colleagues engineered mice with varying allelic doses …