Reading through nonsense

We recently heard a solid journal club presentation about genetic nonsense mutations. Nonsense mutations are point mutations in the DNA sequence that introduce a premature stop (or nonsense) codon and can lead to a truncated protein (or, in many cases, no protein at all as nonsense codons are detected by the presence of exon-junction complexes and the mRNA is degraded). The paper discussed described a drug, PTC124, that is entering the final phase of clinical trials that supresses premature termination and allows readthrough of nonsense codons by the translational machinery and production of a full-length protein.

What does this have to do with cancer? The paper discusses the therapeutic potential of the drug in terms of cystic fibrosis and muscular dystrophy - two diseases with pathology known to be caused (at least in some cases) by nonsense mutations in specific genes; CTFR for cystic fibrosis and dystrophin for muscular dystrophy. An obvious target for cancer therapeutics is p53. The p53 gene is mutated in over 50% of human tumours and of those mutants, almost 8% are nonsense mutations (source:IARC p53 mutation database). Research has shown that reactivation of p53 has therapeutic potential in mouse models of cancer, leading to growth arrest and regression of tumours. One need not limit this idea to p53. Nonsense mutations in many other genes, such as BRCA or Rb, have been associated with cancer and bypass of nonsense-mediated decay represents an interesting area to explore when dealing with cancer, and other, therapeutics.