All Roads Lead to Rome: YAP/TAZ Activity Influences Efficacy of KRASG12C Inhibitors.

Abstract

The development of direct inhibitors of KRASG12C represents a monumental step forward in the field of oncology. Nevertheless, there is considerable opportunity to enhance response rates to KRASG12C inhibitors. In this issue of Cancer Research, three investigative teams explore the modulation of KRASG12C inhibitor activity in lung, colorectal, and pancreatic cancers using CRISPR-based knockout screens. While each group identified and validated a variety of genes and pathways conferring resistance to KRASG12C inhibition, all three groups converged upon activation of YAP/TAZ as a common means of resistance. While coinhibition of KRASG12C and YAP/TAZ did not cause complete tumor regression in xenograft models, combining YAP/TAZ inhibition was capable of significantly extending the response of tumors to KRASG12C inhibition. See related articles by Mukhopadhyay et al., p. 4095, Edwards et al., p. 4112, and Prahallad et al., p. 4130.