One of a new generation of cancer therapies that work by disrupting the specific molecular target responsible for stimulating tumour growth, gefitinib acts on the receptor for the epidermal growth factor protein (EGFR) to halt the spread of cancer cells.
Gefitinib works by fitting into the activating pocket of the protein, blocking the growth signals and thereby depriving the cancer cells of the stimuli they need to survive.
"It appeared that the tumours in cancer patients bypassed the effects of gefitinib,” explains Balazs Halmos, MD, a physician-scientist. Halmos identified a 71-year-old patient, who had recently relapsed after two years of complete remission while undergoing gefitinib therapy with advanced NSCLC.
Halmos and Daniel Tenen, MD, a molecular biologist at BIDMC, and Susumu Kobayashi, MD, PhD, a physician-scientist, obtained a second biopsy of the tumour and sequenced the EGFR tyrosine kinase domain.
Their studies confirmed the existence of a second mutation, and insertion of this mutation into test cells rendered them resistant to gefitinib in vitro. Further analysis revealed that the newly identified mutation was altering gefitinib's drug-binding pocket and thereby changing the keyhole so that the key gefitinib no longer fit.
"The development of a second mutation suggests that the tumour cells remain dependent on an active EGFR pathway for their proliferation,” explains Tenen, Professor of Medicine at Harvard Medical School.
"We're now in the process of planning clinical studies to test novel EGFR inhibitor compounds in lung-cancer patients whose tumours have become resistant to gefitinib”, says Johnson.
MEDICA.de; Source: Beth Israel Deaconess Medical