How tumour cells acquire resistance to drugs 7/3/05. By the Public Library of Science Lung tumours are found to become resistant to two drugs when they acquire a new genetic mutation.

Acquired resistance to chemotherapy is a major obstacle to successful cancer treatment. Understanding the mechanisms by which tumours become resistant to a particular agent is key to identifying new drugs or combination regimens.

Kinases are signaling molecules that control many aspects of cell behavior, including cell proliferation – whether and how fast cells divide. Abnormally active kinases promoting tumour growth are found in many cancers and are a focus of rational cancer drug design.

One target for kinase inhibitors is the epidermal growth factor receptor (EGFR). Two EGFR inhibitors, gefitinib and erlotinib, showed therapeutic benefits in a subset of patients with non-small cell lung cancer. Recent work has helped us understand why some patients respond and some don't: responsive tumours usually have activating mutations in the EGFR gene, which somehow make the tumours sensitive to treatment.

Nearly all patients whose tumours initially respond to EGFR inhibitors, however, eventually become resistant to the drugs and progress despite continued therapy.

William Pao and colleagues 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 and, 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 biopsies from these patients taken before treatment, nor in over 150 lung cancer samples from patients who had not been treated with either drug.

It is clear, though, that this is only one mechanism of resistance, 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.

All kinases share some common features, and a resistance mutation very similar to the one identified here 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. Similarly, the results by Pao and colleagues should help researchers develop second generation drugs for lung cancer.

Adapted from an article by the Public Library of Science: How Tumor Cells Acquire Resistance to Kinase Inhibitors. PLoS Med 2005 2(3): e74.

Further reading

Pao W et al. Acquired Resistance of Lung Adenocarcinomas to Gefitinib or Erlotinib Is Associated with a Second Mutation in the EGFR Kinase Domain. PLoS Med 2005 2(3): e73. Full text

Clark J, Cools J, Gilliland D. EGFR Inhibition in Non-Small Cell Lung Cancer: Resistance, Once Again, Rears Its Ugly Head. PLoS Med 2005 2(3): e75. Full text