The EGFR-RAS-ERK signaling cascade has fundamental relevance for colorectal cancer (CRC) biology and therapy response. However, no targeted therapy options are available for patients with KRAS-mutant CRC. This is because these cancers are intrinsically resistant to EGFR inhibition, as well as therapeutic inhibition of downstream signaling nodes. Therapies targeting the RAS-ERK network generally result in ERK reactivation through dynamic changes in the signaling network. We have shown previously that activity of the signaling network converging on ERK is intrinsically coupled to cell differentiation in CRC.

In this application, we hypothesize that ERK activity is a suitable read-out to detect resistant CRC cell states emerging during targeted therapy. To test this hypothesis, we will analyze heterocellular CRC organoids with single-cell methodologies established in our lab: CyTOF, single-cell RNA sequencing and fluorescent reporters.