Genetic Test Determines Patients Sensitivity to Cancer Drug

The identification of genetic biomarkers of synthetic lethal drug sensitivity effects provides one approach to the development of targeted cancer therapies. Testing for a gene commonly mutated in ovarian cancers could pick out patients who will respond well to a promising new class of cancer drugs.

Oncogene activation can induce replication stress and reliance upon an Ataxia-Telangiectasia protein (ATR) checkpoint function and this provides one rationale for the use of small molecule ATR inhibitors (ATRi) as cancer therapeutics.

A team of scientists at the Institute of Cancer Research have demonstrated that defects in AT-Rich Interaction Domain 1A (ARID1A) sensitize tumor cells to clinical inhibitors of the DNA damage checkpoint kinase, ATR, both in vitro and in vivo. The team used a multiplicity of techniques including cell lines, ribonucleic acid screening, Western blots and antibodies, cellular viability assays, and immunofluorescence using a confocal microscope. Some samples were analyzed on a BD LSR II flow cytometer.

The scientists found that found that ATR inhibitors stopped cancer cells with ARID1A mutations from growing, both in culture dishes and in mice. They also found that switching off the ARID1A gene in breast and bowel cancer cells greatly increased their sensitivity to ATR inhibitors. They found the treatment killed cancer cells with ARID1A mutations through a process called 'synthetic lethality'. Patients on clinical trials of ATR inhibitors could now start to be tested for ARID1A mutations in their tumors in order to assess whether those with the genetic defects are particularly likely to benefit.

Justine Alford, PhD, a senior science information officer for Cancer research UK, said, “By identifying a potential way to exploit a specific genetic vulnerability in cancer this study could point the way to tailoring treatments to each patient, helping to make them kinder and more effective. The next steps will be to better understand the effects of targeting this weakness, and to find out whether this promising strategy will work in people.” The study was published on December 13, 2016, in the journal Nature Communications.