Editors' ChoiceCancer

A Preemptive Strike Against Resistant Tumor Cells

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Science Translational Medicine  10 Feb 2010:
Vol. 2, Issue 18, pp. ec23
DOI: 10.1126/scitranslmed.3000924

Six decades have passed since the first use of chemotherapy to treat cancer. Yet, most cancers still cannot be cured with chemotherapy alone—tumors shrink initially, only to resume growth later. Inhibitors of receptor tyrosine kinases demonstrate remarkable therapeutic activity, especially against tumors that carry mutations—either a translocation (for example, Bcr-Abl) or point mutation (for example, Kit and EGFR)—in the gene that encodes the drug-targeted receptor. But even inhibitors of receptor tyrosine kinases are rarely curative. In lung cancer patients who are treated with either reversible or irreversible inhibitors of the epidermal growth factor receptor (EGFR), tumors eventually develop drug resistance either by acquiring new mutations in the EGFR gene or via the bypass pathway: amplification of the MET gene, which encodes the hepatocyte growth factor (HGF) receptor. Prior knowledge of the mechanism by which a particular tumor will acquire drug resistance may guide the development of tumor-specific therapy regimens. To this end, Jänne and colleagues have deciphered one parameter that determines the path toward resistance that a specific lung tumor will take.

The authors identified a lung cancer cell line (HCC827) that reproducibly develops resistance to an inhibitor of the EGFR tyrosine kinase via MET gene amplification. These genetic gyrations manifest during prolonged treatment with the tyrosine kinase inhibitor alone and when this drug is combined with HGF. The researchers then investigated why HCC827 cells undergo MET amplification when, under these same conditions, other cancer cell lines don’t. High-throughput fluorescence in situ hybridization assays revealed that small numbers of MET-amplified clones exist in the HCC827 cell line even before treatment. By mixing green fluorescent protein–labeled, MET-amplified tumor cells into the HCC827 cultures, the authors directly demonstrated selective expansion of the former in the presence of an EGFR tyrosine kinase inhibitor. Remarkably, rare MET-amplified cells were unearthed in all four pretreatment tumor samples isolated from patients who later developed resistance to an EGFR tyrosine kinase inhibitor through MET amplification, but in only one of eight patients who developed resistance through other mechanisms.

These results show that by analyzing the genetic profile of rare mutant clones present in a tumor, it may be possible to predict a tumor’s preferred drug-resistance mechanism even before treatment. For a patient who is destined to develop resistance via MET amplification, it may be beneficial to add a MET inhibitor to their initial therapeutic cocktail, possibly nipping resistance in the bud.

A. B. Turke et al., Preexistence and clonal selection of MET amplification in EGFR mutant NSCLC. Cancer Cell 17, 77–88 (2010). [Abstract]

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