Lung cancer is the leading cause of
cancer death among both men and women in the United States. Because
lung cancer is genetically heterogeneous, tailored
therapy alone or in combination with
chemotherapy would increase patient overall survival as compared with the one-size-fits-all
chemotherapy. TP53-mutant
lung cancer accounts for more than half of all
lung cancer cases and is oftentimes more aggressive and resistant to
chemotherapy. Directly targeting mutant p53 has not yet been successful, so identification of novel
therapy targets and
biomarkers in the TP53-mutant
lung cancer is urgently needed to increase the overall survival in this subgroup.
Deubiquitinating enzymes (DUBs) regulate a vast majority of
proteins (DUBs' substrates) via removal of
ubiquitin moieties or
ubiquitin chains from these
proteins, thereby altering the stability and/or functions of these substrates. In this review, we will focus on a DUB, referred to as
ubiquitin-specific peptidase 10 (USP10) whose substrates include both oncogenic
proteins and
tumor suppressors. Therefore, targeting USP10 in
cancer is highly context-dependent. Here, we will discuss USP10's functions in
cancer by examining its various known substrates. In particular, we will elaborate our recent findings in the oncogenic role of USP10 in the TP53-mutant subgroup of
lung cancer, focusing on USP10's function in the DNA damage response (DDR) via
histone deacetylase 6 (HDAC6). Overall, these findings support the notion that targeting USP10 in the TP53-mutant subgroup of NSCLC would sensitize patients to
cisplatin-based
chemotherapy. Generating potent and specific clinically relevant USP10 inhibitors would benefit the TP53-mutant subgroup of NSCLC patients.