Understanding the mechanisms by which tumours become resistant to a particular agent is key to identifying new drugs or combination regimens. While the problem of resistance will always be an ongoing problem for the pharmaceutical industry, new strategies and points of attack will ensure the fight against resistance will be an equal one.
Led by William Pao, scientists (from the Memorial Sloan-Kettering Cancer Centre in New York) have begun to shed light on what causes resistance to two recently approved lung cancer drugs, Iressa (gefitinib) a kinase inhibitor and Tarceva (erlotinib), an epidermal growth factor receptor (EGFR) kinase inhibitor. Both of them have shown therapeutic benefits in a subset of patients with lung cancer.
The study along with recent work has helped to understand why some patients respond and some do not. Responsive tumours usually harbour activating mutations in the EGFR gene, which somehow make the tumours sensitive to treatment. Nearly all patients whose tumours initially respond to the drugs, however, eventually become resistant to the drugs and progress despite continued therapy. The results by Pao and colleagues should help researchers develop second-generation drugs for lung cancer.
Scientists examined tumours from six patients with non-small cell lung cancer who initially responded to gefitinib or erlotinib but subsequently relapsed. Tumours from all six patients carried activating mutations in the EGFR gene. In addition, in three out of the six cases, the resistant tumour cells carried an identical second mutation in the EGFR gene.
Whereas the activating mutation was present in tumour cells before treatment with erlotinib or gefitinib, the second mutation was not found in pre-treatment biopsies from these patients, or in over 150 lung cancer samples from patients who had not been treated with either drug.
Additional cell culture studies supported the notion that the secondary mutation causes resistance to gefitinib or erlotinib. It is clear, though, that this is only one of several resistance mechanisms, because in the three other cases resistance occurred in the absence of the second mutation. What caused the resistance in those tumours is not known.
kinases share a resistance mutation very similar to the one identified here. In addition, the mutation has also been found in other kinase genes from tumours with acquired resistance to imatinib, another kinase inhibitor.
The initial identification three years ago of resistance mutations against imatinib led to the rapid development of alternative kinase inhibitors that work even against tumours with the resistance mutation.
The study went onto conclude that larger studies were needed to confirm that this particular mutation is a major cause of resistance against the two drugs. It is also important to find out what causes resistance in the other cases. Knowing about this resistance mutation will help researchers to develop drugs that will work even against tumours with the mutation.