Editors' ChoiceCancer

Attacking Lung Cancer, One Mutation at a Time

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Science Translational Medicine  10 Nov 2010:
Vol. 2, Issue 57, pp. 57ec176
DOI: 10.1126/scitranslmed.3001885

In the era of Hippocrates, doctors were taught to treat each patient as if he or she had a unique disease. Nearly 2400 years later, the era of personalized medicine in cancer—in which treatment is tailored to the unique characteristics of a patient's tumor—has truly begun. Take lung cancer, for example. Until a few years ago, lung cancer was divided into a handful of types on the basis of histological appearance: small cell carcinoma, adenocarconima, large cell carcinoma, and squamous cell carcinoma. The latter three types all were treated in the same way and thus were grouped under the nebulous designation of non–small-cell lung cancer. Now, an international group of lung cancer researchers report, in the New England Journal of Medicine, the results of an early clinical trial of a drug that targets a specific genetic aberration found in 3 to 5% of lung adenocarcinoma patients.

The first breakthrough in personalized lung cancer treatment came when researchers revealed that some adenocarcinomas carry mutations in the epidermal growth factor receptor (EGFR). These tumors were uniquely responsive to EGFR inhibitors gefitinib and erlotinib, which until then had been used in all non–small-cell lung cancer patients with unimpressive results. This finding led to widespread screening for EGFR point mutations, which are now assessed in every patient with lung cancer. Another step forward came with the discovery, in ~5% of lung adenocarcinomas, of the EML4-ALK translocation—in which a fragment of the echinoderm microtubule-associated protein-like 4 gene (EML4) is fused with a part of the anaplastic lymphoma kinase gene (ALK). This translocation event results in constitutive activation of the ALK protein, a receptor tyrosine kinase. Crizotinib, an ALK inhibitor developed by Pfizer, was tested in a panel of hundreds of lung cancer cell lines and found to inhibit only EML4-ALK–positive cell lines. First-in-human phase I clinical trials were later initiated to test crizotinib in cancer patients.

Because the primary aim of a phase I trial is to assess the safety of a drug, all patients with solid tumors were enrolled in the study. However, two patients with EML4-ALK–positive lung cancer had dramatic therapeutic responses to crizotinib, and an effort was initiated to enroll translocation-positive patients in the trial. Out of 1500 patients screened, 82 were identified with EML4-ALK translocation—positive lung tumors. In these patients, who had already failed standard therapies, treatment with crizotinib resulted in significant tumor shrinkage (57% of the patients) and, in one patient, a complete disappearance of the tumor.

Further work will focus on overcoming the eventual development of drug resistance, which has been a challenge for all tyrosine kinase inhibitors used to treat cancers. Indeed, resistance mutations have been detected in a patient who initially responded to crizotinib and subsequently relapsed, as described in a companion article by Choi et al. in the same issue of the journal. However, despite the challenges ahead, researchers believe that, one day, every cancer patient will be analyzed for a panel of markers that predicts the response of his or her tumor to a variety of targeted anticancer agents. Hippocrates would be proud of us.

E. L. Kwak et al., Anaplastic lymphoma kinase inhibition in non–small-cell lung cancer. N. Engl. J. Med. 363, 1693–1703 (2010). [Abstract]

Y. L. Choi et al., EML4-ALK mutations in lung cancer that confer resistance to ALK inhibitors. N. Engl. J. Med. 363, 1734–1739 (2010). [Abstract]

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