In Reply We appreciate the important data put forth by Renaud and colleagues. They report that preclinical data suggest 2 main groups of KRAS-mutated cells—one dependent from KRAS mutations and the other not—and that this should be taken into account when attempting direct inhibition as a therapeutic modality. We agree that this is important. We would emphasize that in identifying these 2 main groups of KRAS-mutated cells, Singh and colleagues1 note the strong correlation between KRAS protein amplification and KRAS-dependent cell lines. We are of the opinion that future clinical trials should identify whether KRAS protein amplification is present in the molecular testing of their participants because this could provide evidence of whether KRAS-dependent vs KRAS-independent cells are present. Evaluating response rates in patients with KRAS-amplified vs nonamplified disease could provide important clinical information. Importantly, while these data should be taken into account, we believe that it should not dissuade investigators from moving forward with new attempts at direct inhibition of oncogenic KRAS, especially given the overwhelming data present in in vitro, in vivo, and mouse models that suppression of KRAS by RNA interference impairs growth of KRAS-mutant cell lines.2,3 We also emphasize that KRAS signaling is relatively complex, and in the future, we should take into account the systems biological characteristics as related to KRAS.