USP10 is an important factor in the progression of colorectal cancer, as inhibition or silencing of USP10 attenuates the aggressive phenotype. USP10 regulates sensitivity to the two widely used EGFR inhibitors gefitinib and osimertinib. Mechanistically, we show that USP10 mediates its effects via the phosphatase INPP4B, which regulates the downstream PI3K/AKT/mTOR signaling pathway. Thus, our study demonstrates for the first time a novel link between USP10 and response to EGFR-targeted therapy.