Testing for mutations in ARID1A, a gene that is commonly mutated in ovarian cancers, may help predict which patients are likely to respond to a novel class of drugs currently in clinical development, new research found.
The study, “ATR inhibitors as a synthetic lethal therapy for tumours deficient in ARID1A,” published in Nature Communications, shows that these drugs, called ATR inhibitors, can halt the growth of cancer cells with ARID1A mutations, both in culture and in mice.
“By identifying a potential way to exploit a specific genetic vulnerability in cancer this research could point the way to tailoring treatments to each patient, helping to make them kinder and more effective,” Dr. Justine Alford, Cancer Research UK’s senior science information officer, said in a press release.
ATR is a critical component of the cellular machinery that is involved in DNA damage response and in preventing the cells from dividing when DNA damages exist. In cancer, the exacerbated cell proliferation often renders the cells more dependent on these ATR functions, suggesting that blocking ATR could be a promising approach to help treat a number of cancers.
Currently, ATR inhibitors are already in clinical trials for solid tumors, but researchers lacked useful biomarkers that predicted which patients would respond better to such therapies.
Now, a team at The Institute of Cancer Research in London found that cancer cells with ARID1A mutations were particularly more sensitive to ATR inhibitors, both in culture and in mice beating ARID1A-mutated colon cancer.
Switching off the expression of ARID1A in breast and bowel cancer cells also rendered these cells more sensitive to the inhibitors.
The process by which ARID1A mutations induced sensitivity to ATR inhibitors was called “synthetic lethality,” which occurs when inactivation of two seemingly unrelated genes leads to cell death. Researchers found that when the two proteins were inactivated, the cancer cells divided prematurely, which lead to high DNA instability and cell death.
“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,” Alford said.
Now, the researchers believe that patients on clinical trials for ATR inhibitors should be tested for mutations in ARID1A to assess whether those with those genetic defects are more likely to benefit from such drugs.
“This early finding could bring us a step closer to more ‘personalized’ medicine, targeting treatment to exploit weaknesses in patients’ tumors and hopefully improve their chances of survival,” said Katie Goates, senior research communications officer at Breast Cancer Now.
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