According to a major new study, by testing for a gene that mutates in ovarian
cancers, patients could be picked out who will respond well to a promising new class of
cancer drugs. The scientists have found that defects in a gene called ARID1A caused
sensitivity to new drugs targeting the DNA repair process that is within the tumor cells.
This new drug is called ATR inhibitors and is already being tested in some early
clinical trials. The new research could help identify those patients who will most benefit.
The Institute of Cancer Research scientists in London used molecular screening
techniques to find that cancers with mutations in ARID1A were especially sensitive to
ATR inhibitors.
ARID1A is mutated in a wide range of hard-to-treat tumor types that include
ovarian cancer and stomach cancer. There has been no way of targeting treatment at
tumors with this genetic defect until now. This research is published in the journal
Nature Communications and was funded by the Cancer Research UK and Breast
Cancer Now.
The Institute of Cancer Research (ICR) scientists found that ATR inhibitors
stopped cancer cells with ARID1A mutations from growing in the culture dish and in
mice. It was also found that switching the ARID1A gene in breast and bowel cancer
cells increased their sensitivity to ATR inhibitors greatly.
The researchers also found that the treatment killed the cancer cells with
ARID1A mutations through a process called “synthetic lethality.” Those cancer cells
with ARID1A mutations become particularly reliant on the DNA safeguarding activity of
the ATR protein to survive, so they are especially sensitive to drugs that block its
effects.
The testing for ARID1A mutations in their tumors could now start to be tested on
those patients on clinical trials of ATR, to assess whether those with the genetic defects
are particularly likely to benefit. Leader of the Gene Function Team at The Institute of
Cancer Research, Dr. Chris Lord, says that their research has opened up a potential
way of personalizing treatment for cancer by targeting drugs to those patients who will
benefit the most.
Cell cultures were found in mice that cancers with defective versions of the
ARID1A gene are particularly sensitive to a new class of drug called the ATR inhibitors.
This research could lead to patients with ARID1A mutant tumors being assessed for
whether they respond particularly well to this new class of treatment for cancer.
Cancer Research UK’s, Dr. Justine Alford, senior science information officer, said
that by identifying a potential way to exploit a specific genetic vulnerability in cancer that
this research could point the way to tailoring treatments for each patient to help make
them kinder and more effective. Better understanding the effects of targeting this
weakness would be the next step and to find out whether this promising strategy will
work in people. This 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.
It is very promising and exciting that an idea that was initially tested in breast
cancer cells might be translated into potential benefits for a number of other cancers as
well. This can be the groundwork for clinical trials to investigate the potential of ATR
inhibitors as a targeted cancer treatment in the near future.
Dr Fredda Branyon