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WEE-ding out cancer

It is well known that mutations drive cancer cell growth and resistance to treatment.  However, these mutations can also become a weak point, or Achilles’ heel, for a tumour. Now, scientists at the University of Oxford have found a new way to kill cancer cells with mutations in a key cancer gene called SETD2.

Study author, Dr Timothy Humphrey said “Mutations in SETD2 are frequently found in kidney cancer and some childhood brain tumours, so we were excited when we discovered that a new drug we were studying specifically killed cancer cells with this mutation”.

In work published in Cancer Cell online today, Dr Tim Humphrey and his team showed that cancer cells with a mutated SETD2 gene were killed by a drug (AZD1775) that inhibits a protein called WEE1, which was first discovered by Nobel Prize winner, Sir Paul Nurse. 

They have achieved this by exploiting the concept of ‘synthetic lethality’, which has the potential to be a less toxic and more effective treatment than more standard approaches because it specifically targets cancer cells.

Importantly, the research team have also developed a biomarker test to identify SETD2 mutated tumours and, therefore, these findings have immediate clinical relevance. 

Professor Tim Maughan, Clinical Director of the CRUK/MRC Oxford Institute for Radiation Oncology, commented “This novel and exciting finding provides a new scientific basis for precision targeting of some cancers which are currently very difficult to treat, and we are now taking these findings into clinical trials”.

These findings may also help to target other cancers with similar weak points and provide a step towards personalised cancer therapy.

Previous work had shown that WEE1 was critical for regulating cell division, but the mechanism by which WEE1 inhibition killed tumour cells with SETD2 mutations turned out to be a surprise. To grow, cancer cells need to duplicate their DNA using newly synthesised building blocks called deoxynucleotides. 

When WEE1 was inhibited in cells with a SETD2 mutation, the levels of deoxynucleotides dropped below the critical level needed for DNA replication and - starved of these building blocks - the cells die”, said study co-author, Dr Andy Ryan.  “Importantly, normal cells in the body do not have SETD2 mutations, so these effects of WEE1 inhibition are potentially very selective to cancer cells”.

The work will be presented at the NCRI conference in Liverpool, UK on 2 November 2015.

The full research paper, Inhibiting WEE1 Selectively Kills Histone H3K36me3-Deficient Cancers by dNTP Starvation, is published in the journal Cancer Cell: doi: 10.1016/j.ccell.2015.09.015

Image: H3K36me3-deficient cancers can be specifically targeted by inhibitors of WEE1, ATR or CHK1. Treatment of H3K36me3-deficient cancers with checkpoint kinase inhibitors (right panel) results in dNTP starvation (coloured red, green blue and yellow), leading to DNA replication fork collapse (illustrated), and apoptosis.

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