Reply to Tran et al.: Dimeric KRAS protein-protein interaction stabilizers.

We thank Tran et al. (1) for their appreciation of our open innovation platform (https://opnme.com/) and interest in our manuscript (2) in which we demonstrate that the small-molecule KRAS inhibitor BI-2852 reduces pERK (EC50 = 6 µM) and inhibits proliferation (EC50 = 7 µM) in NCI-H358 cells. Tran et al. (1) propose that BI-2852 exerts its cellular effects on the MAPK pathway at least in part through stabilization of a nonfunctional KRAS dimer. No cellular data for KRAS dimer induction are provided and the hypothesis is primarily based on KRAS dimer formation observed with size exclusion chromatography using concentrations 1,000 times higher (3 mM) than those in which the cellular effects of BI-2852 are observed. Hence, inhibiting the protein–protein interactions between KRAS and its GEFs, GAPs, and downstream effectors is a more plausible explanation than … \n\n[↵][1]1To whom correspondence should be addressed. Email: darryl.mcconnell{at}boehringer-ingelheim.com.\n\n [1]: #xref-corresp-1-1