SMK-002 inhibits the growth of bladder cancer cells and increases their sensitivity to Osimertinib <i>via</i> enhancing epidermal growth factor receptor degradation

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 <i>in vivo</i> and <i>in vitro</i> 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 <i>in vitro</i> and <i>in vivo</i>, providing a novel strategy for the potential treatment of BC.