Molecular Rationale For Erk And Egfr Inhibition In Colorectal Cancer.

679Background: Mutational activation of the RAS pathway occurs in u003e50% of human CRC tumors, and to date has been difficult to overcome. We recently identified receptor tyrosine phosphatase-S (PTPRS) as an important regulator of the RAS pathway, which is mutated in ~11% of CRC. Methods: Global gene expression and DNA sequencing data (1321 cancer genes) were integrated across 468 CRC tumors to identify PTPRS as one of the most commonly mutated genes with a high correlation to a RAS activation score. Apoptotic responses to inhibitors of ERK, EGFR and their combination were tested in isogenic wild-type and mutant RAS cell lines where PTPRS had been knocked out by CRISPR. Results: PTPRS was in the top 15 genes correlating with RAS pathway activation scores; as expected, KRAS, BRAF were the most correlated genes. In order to determine the effect of the loss of PTPRS on RAS/ERK signaling, we used CRISPR to knockout PTPRS in an isogenic pair of CRC cell lines (HCT116) with mutant or wild type KRAS. Cell lines lac...