LHX9 rescues KRAS suppression through transcriptional regulation of YAP1 [RNA-Seq]

Oncogenic KRAS signaling is required for tumor survival in cancers that harbor KRAS mutations. We recently performed a genome-scale expression screen to identify genes that bypass KRAS dependency. Here we demonstrate that the developmental transcription factor LHX9 rescues KRAS suppression in vitro and xenograft models. Furthermore, LHX9 decreases cell sensitivity to KRASG12C and MEK1/2 inhibitors. LHX9 promotes transcriptional changes associated with KRAS. Importantly, YAP1 upregulation by LHX9 is required for the rescue of KRAS suppression. Together we identify LHX9 as a YAP1 transcriptional regulator that permits KRAS-dependent cells to proliferate without KRAS expression. Overall design: mRNA profiles of HCT116 cells expressing different open reading frames and tet-inducible shKRAS were generated by sequencing, in duplicates, using Illumina Hiseq-2500