Targeted therapies: No longer in the dark

signaling update home

SOURCE:

Two studies reveal why only some subsets of patients with cancer are sensitive to the anticancer agent gefitinib, a small-molecule inhibitor of EGFR.

Why are only some subsets of patients with cancer sensitive to the anticancer agent gefitinib? Thomas J. Lynch et al. in the New England Journal of Medicine and J. Guillermo Paez et al. in Science shed light on this question and their findings will help select patients who will benefit from treatment with gefitinib in the future.

Results from early clinical trials with gefitinib — which is a small-molecule inhibitor of the epidermal growth factor receptor (EGFR) — caused great excitment among cancer researchers and clinicians alike. The data indicated that gefitinib would be active against non-small-cell lung cancer (NSCLC), a disease that often has overexpression of EGFR and for which chemotherapy is not very effective. However, large randomized trials only showed responses in a small subset of patients with NSCLC. Because of the rapid and dramatic response seen in this $sim$ 10% of patients, gefitinib is now approved for third-line therapy of NSCLC.

Efficacy of gefitinib does not correlate with EGFR expression, so Lynch et al. hypothesized that mutations within the gene might be present that would distinguish responders from non-responders. Indeed, they found that heterozygous gain-of-function mutations were clustered within the tyrosine-kinase domain of EGFR — the active site where gefitinib binds — in tumour specimens analysed from eight of nine patients who had responded to gefitinib. Four of these patients had in-frame deletions within exon 19, and three of the patients had amino-acid substitutions within exon 21. Matched normal tissue from these patients did not contain the mutations and no mutations were seen in seven patients who had not responded to gefitinib. Paez et al. also examined samples from five patients treated with gefitinib for mutations in EGFR and found mutations similar to those in the study by Lynch et al.

Both papers show correlation of the mutations with certain patient characteristics, which in turn correlate with the subset of patients who respond to gefitinib. In the Paez et al. study, 15 out of 58 patients from Japan had heterozygous mutations in EGFR in their tumour tissue but not in their normal tissue, but only one patient out of 61 from the United States had a heterozygous mutation. This is interesting, because the early clinical trials that showed a 27.5% response rate were conducted in Japan, whereas later trials in Europe showed only a 10.4% response rate. There was also an association seen in both studies between presence of mutations and those responding patients who had bronchoalveolar adenocarcinoma, who were not current smokers and who were women — again the subset of patients known to respond to gefitinib.

Lynch et al. went on to show that transfection of the missense EGFR mutant L858R or the in-frame deletion L747–P753insS into cultured cell lines resulted in 2–3-fold increased stimulation of the receptor by EGF and that activation of the mutant receptor lasted up to 12 times longer when compared with the wild-type receptor. The mutant EGFR proteins were also about 10 times more sensitive to inhibition by gefitinib than wild-type EGFR. Paez et al. investigated a cell line derived from a malignant pleural effusion from a Caucasian female non-smoker with lung adenocarcinoma — the cells had the L858R mutation in EGFR and were 50 times more sensitive to gefitinib than other adenocarcinoma cell lines.

The authors hypothesize that the mutations in EGFR stabilize the interaction between the drug and the kinase, thereby increasing the inhibitory effect of gefitinib. If these data are confirmed in prospective clinical trials, they will set a standard for approaches to the evaluation and use of targeted therapy for solid tumours.

Ezzie Hutchinson

References

Lynch, T. J. et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N. Engl. J. Med. 350, 2129–2139 (2004)
Paez, J. G. et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy Science 304, 1497–1500 (2004)