Patient derived xenograft platform for anti-EGFR secondary resistant colorectal cancers

Molecular mechanisms for secondary resistance (SR) in colorectal cancers (CRCs) under anti-EGFR therapy are largely derived from circulating tumor DNA (ctDNA) and rarely from primary tissue. Here we generated anti-EGFR SR tumors from ten KRAS, NRAS, BRAF, and PI3K wild-type CRC patient derived xenograft (PDX) models and characterized these by whole exome sequencing. We found an unexpected low driver mutations frequency (26%) in SR tumors. However, transcriptomic analyses revealed a strikingly high frequency of RAS-MEK-ERK pathway reactivation via transcriptional reprogramming.