SMK-002, a novel derivative of proguanil, has higher inhibitory activity against cancer than proguanil. We previously found that SMK-002 significantly inhibited the proliferation of bladder cancer (BC) cells. In this study, we creatively found that the sensitivity of BC cells to SMK-002 was positively correlated with the expression of epidermal growth factor receptor (EGFR). Mechanistically, SMK-002 specifically targeted EGFR and inhibited its binding to the deubiquitination protein USP11, facilitated the ubiquitination degradation of EGFR in lysosomes by post-translational modification. Further studies suggested that SMK-002 significantly inhibited the p-EGFR/p-c-Raf/p-ERK downstream pathway. Osimertinib, one commonly used representative of the clinically approved third-generation EGFR inhibitors, has been rarely reported to apply on BC. Furthermore, we found that SMK-002 synergized with Osimertinib further downregulated EGFR signal pathway and reduced growth of BC both in vivo and in vitro without any detectable toxicities. Taken together, this study revealed that SMK-002 inhibited proliferation and migration of BC cells by promoting EGFR ubiquitination degradation in lysosomes. Moreover, SMK-002 synergized with Osimertinib and further inhibited the growth of BC cells both in vitro and in vivo, providing a novel strategy for the potential treatment of BC.
