6533b85cfe1ef96bd12bc9b4

RESEARCH PRODUCT

In the literature: March 2016

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The way clones resistant to anti-EGFR (Epidermal Growth Factor Receptor) inhibition evolve in non-small cell lung cancer is far from being determined. In an international cooperative effort led by investigators at Johns Hopkins Hospital in Baltimore, the origin of acquired resistance mediated by the EGFRT790M mutation has been further elucidated. That mutation, recognised as gatekeeper and present in about 60% of pretreated cases with anti-EGFRs, could occur either from the selection of previously existing EGFR790M cell clones or by the evolution of originally EGFR790M-negative drug-tolerant cells. In a series of elegant experiments, the authors show that these drug-tolerant cells have a diminished apoptotic response to third generation EFFR inhibitors specifically tackling EGFR790M. Moreover, the use of potent inhibitors of the antiapoptotic factors BCL2 and BCL-xL, such as navitoclax, was able to restore sensitivity. Thus, drug-tolerant cells that are capable of surviving initial drug therapy may provide a reservoir of cells from which genetic mechanisms of acquired resistance can evolve. These …