Given the proven difficulty of modifying p53 as a means to control cancer, much research has focused on identifying targets that confer synthetic lethality to tumours that harbour mutations in TP53. Now, researchers have shown that loss of MAP kinase-activated protein kinase 2 (MK2) sensitizes p53-deficient tumours to cisplatin in a realistic animal model.

MK2 is a stress-regulated kinase that normally functions in inflammation. In the absence of functional p53, as is the case in most cancers, the MK2 is pathway is essential to halt cell division, enabling DNA repair and subsequent DNA replication—allowing malignant cells to proliferate. Blocking MK2 was previously shown to enhance cell death in vitro.

The team at the Massachusetts Institute of Technology developed a novel gene-targeting strategy using Cre-mediated recombination to generate otherwise isogenic MK2-proficient and MK2-deficient tumours (of non-small-cell lung cancer) within the same animal, either harbouring TP53 mutations or not. Thus, the synthetic lethality of MK2 loss and p53 loss could be studied in vivo.

Upon treatment with cisplatin, tumour shrinkage was more pronounced in the lesions lacking both functional MK2 and p53 than in those only lacking p53. That is, under the genotoxic stress of chemotherapy, p53-deficient cells lacking MK2 were unable to sustain growth, confirming that co-deficiency is a lethal combination. Importantly, p53-proficient cells were unaffected by cisplatin.

These results suggest that MK2 might be a viable target, blockade of which might render TP53-deficient tumours sensitive to therapy.