Response to gefitinib determined by gene mutation
Researchers have discovered specific gene mutations that could be used to identify which lung cancer patients will respond to treatment with gefitinib (Iressa).
Gefitinib, a tyrosine kinase inhibitor, was approved in the US last year
for the treatment of advanced non-small-cell lung cancer (NSCLC).
Trials showed that most patients with lung cancer have no response to
the drug, but the drug was approved because about 10 per cent of patients
have a rapid and often dramatic response.
Researchers screened tumour samples from patients who participated in
these clinical trials and found a mutation in the epidermal growth factor
receptor (EGFR) in eight out of nine patients who responded to the drug.
No EGFR mutations were seen in the seven patients who did not respond
to gefitinib (P<0.001). All the mutations occurred in the same area
of the gene and, in vitro, these mutations demonstrated enhanced tyrosine
kinase activity in response to epidermal growth factor and were 10 times
more sensitive than normal receptors to inhibition by gefitinib.
The researchers detected similar mutations in tumours from two out of
25 patients with NSCLC who had not been exposed to gefitinib (8 per cent).
They suggest that these mutations account for most responses to gefitinib
reported in clinical studies, and diagnostic testing could now be developed
to predict which patients will respond to treatment.
Thomas Lynch, director of the Massachusetts General Hospital thoracic
oncology centre and a co-lead author of the paper, said: “These
findings will help determine which patients will benefit from Iressa
and which should not receive it. In addition, if we know that a patient
is likely to respond, we might be able to start treatment earlier with
this drug that is more effective and has fewer side effects than standard
chemotherapy.”
The researchers also say that structural analysis of the mutant receptors
will help the design of more potent drugs targeting these receptors.
The study is due to be published in the 20 May edition of the New
England Journal of Medicine.
Further evidence Similar
research was published online in Science last
week. Researchers found EGFR mutations in 15 out of 58 non-small-cell
lung tumours in patients from Japan, and in one out of 61 tumours in patients
from the US. Since treatment with gefitinib has been found to be more effective
in Japanese patients, the researchers suggest that EGFR mutations may predict
sensitivity to the drug. They also found EGFR mutations in additional lung
cancer samples from patients in the US who had responded to gefitinib,
and in a lung
adenocarcinoma cell line that was hypersensitive to growth inhibition by the
drug.
|
|
The
Pharmaceutical Journal
Acrobat
Reader