Acquired Resistance to Crizotinib from a Mutation in CD74-ROS1

To the Editor: The important findings of Awad et al. (June 20 issue)(1) regarding the G2032R mutation as a cause of crizotinib resistance in lung cancer suggest an intriguing hypothesis. Despite good tumor-cell content, the allele frequencies of the mutation were very low in some tumor regions and metastases (see Fig. S2 in the Supplementary Appendix, available with the full text of the article at NEJM.org), strongly suggesting that the mutation was subclonal. This finding challenges the prevailing concept that metastases are descendants of a single founder cell. A tenable alternative is that the subclone harboring the G2032R mutation may ...