Though RAS/RAF-dependent cancer cells are refractory to SHP2i monotherapy 147, SHP2i blocks EGFR-mediated MAPK rebound and confers sensitivity in BRAFi resistant CRC cells 138, 148, and synergizes with MEKi to suppress PDAC and NSCLC growth 149, 150. Here, RAF1 is linked to colorectal carcinoma.