The protein tyrosine phosphatase SHP2 plays a key role in activating RAS signaling, but its inhibitors are widely resistant in colorectal cancer (CRC). We reveal WWP1-PTEN-AKT signaling pathway is involved in the resistance of SHP2 inhibition. Combined inhibition of WWP1 and SHP2 exerts a synergistic lethal effect in CRC cells. Expression levels of WWP1 and SHP2 contribute to prognostic modeling in CRC patients. These findings may assist in individual clinical decision-making and clinical trial design, especially for patients with KRAS-mutant CRC.