Drugs target tumour cells with BRCA and PTEN mutations

21 September 2009

A group of drugs have already been shown to be able to specifically target cancer cells containing BRCA mutations via a mechanism known as synthetic lethality, and early clinical trials have shown encouraging results (see previous news). New research published in EMBO Molecular Medicine has demonstrated that these PARP inhibitors can also function as selective inhibitors of tumours in cells with PTEN mutations. 

The phosphatase and tensin homolog (PTEN) gene is a tumour suppressor gene; loss of PTEN gene expression is significantly associated not only with BRCA1-associated familial breast cancers [Saal LH et al. (2008) Nat Genet. 40(1):102-7], but also with various sporadic (non-familial) cancers. It is one of the most commonly mutated genes in human tumours, including breast, prostate, melanoma (skin), endometrial and colon cancers.

Researchers from the Institute of Cancer Research (ICR) in London showed that human cellswith PTEN mutations, like those with BRCA1/2 mutations, are defective in the normal process by which double-stranded breaks in cellular DNA are repaired [Mendes-Pereira AM et al. (2009) EMBO Mol. Med. DOI 10.1002/emmm.200900041]. PARP inhibitors increase the rate of formation of double-stranded breaks in the DNA and thereby selectively target cells with these mutations over normal healthy cells. Selective drug action of this type is not only good news for efficacy, but also reduces the level of toxic side-effects for patients.

The researchers found that human tumour cells with defective PTEN genes were up to 25 times more sensitive to PARP inhibitor drugs than normal cells. They also transplanted human cells with PTEN mutations into mice; growth of the transplanted tumours was significantly suppressed in mice treated with the PARP inhibitor olaparib, but this effect was not seen in mice with tumours arising from human cells without PTEN mutations. The authors therefore propose that PAP inhibitors such as olaparib may be effective against human tumours containing PTEN mutations.

Researcher Professor Alan Ashworth, Director of the ICR Breakthrough Breast Cancer Research Centre commented: “Clinical trials have already shown the potential of PARP inhibitors for patients with tumours caused by faulty BRCA genes. We now need to test whether the promising results from this study can be matched in the much larger group of patients with PTEN-related tumours” (see press release).

Comment: The potential opportunities for new forms of personalised cancer therapeutics continue to expand; of note, treatments that rely on genetic features of the tumour will require tumour testing to assess these features. There may be challenges in communicating to the general public that any new ‘wonder-drugs’ will only be suitable for use in patients whose tumours have the relevant genetic feature/s.

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