Editors' ChoiceCancer

Roots and routes of resistance

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Science Translational Medicine  09 Mar 2016:
Vol. 8, Issue 329, pp. 329ec42
DOI: 10.1126/scitranslmed.aaf3864

The discovery of epidermal growth factor receptor (EGFR) inhibitors as effective therapy for tumors with EGFR- activating mutations ushered in the era of targeted therapy in lung cancer. Unfortunately, resistance to currently available targeted therapy is all but inevitable. Although there are several known molecular mechanisms of acquired resistance to EGFR inhibitors, the most common one is the EGFRT790M gatekeeper mutation, which accounts for 50 to 60% of resistant cases. Third-generation EGFR inhibitors that specifically target EGFRT790M are already on the market, yet very little is known about how these resistant clones evolve in the first place.

Hata and colleagues now report two biologically distinct mechanisms by which resistant clones emerge during therapy with EGFR inhibitors. The authors monitored the evolutionary patterns of resistance in EGFR-mutant lung cancer cells exposed to increasing concentrations of EGFR tyrosine kinase inhibitor gefitinib. They observed marked variations in the rate of development of resistance, with some cells developing resistance early and others late. Additional studies indicated that early resistant EGFRT790M clones emerged from EGFRT790M-mutated cells that already existed among parental cells, whereas late resistant cells developed de novo from initially EGFRT790M-negative cells after prolonged exposure to gefitinib. The late resistant cells had epigenetic hallmarks of a drug-tolerant state and demonstrated a weakened apoptotic response to third-generation EGFR inhibitors. The apoptotic response was restored when late resistant cells were treated with an inhibitor of the BCL2 family of antiapoptotic factors, navitoclax, in combination with third-generation EGFR inhibitors, suggesting an important role for the specific evolutionary mechanism of resistance in determining response to subsequent therapies.

Although it was performed in a limited panel of cell lines, this study provides initial evidence of the presence of a drug-tolerant population of cells that persist in tumors during treatment and then undergo further evolution to acquire resistance. New therapeutic strategies aimed specifically at these cells before they evolve could help prevent or delay the evolution of acquired resistance.

A. N. Hata et al., Tumor cells can follow distinct evolutionary paths to become resistant to epidermal growth factor receptor inhibition. Nat. Med. 22, 262–269 (2016). [Abstract]

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