In Cancer Discovery this week, researchers in Canada and Italy report essential gene profiles of various cancer types. The team used a lentiviral library of short hairpin RNA targeting 16,000 genes and a new dynamic scoring approach to identify the essential gene profiles in 72 breast, pancreatic, and ovarian cancer cell lines. "Integrating our results with current and future genomic data should facilitate the systematic identification of drivers, unanticipated synthetic lethal relationships, and functional vulnerabilities of these tumor types," the authors write.
Also in Cancer Discovery this week, a team of US researchers reports a mechanism for the inhibition of apoptosis in glioblastoma. The TRAIL apoptotic pathway has emerged as a possible therapeutic target for certain cancers, but clinical trials have shown that the majority of cancers are resistant to such treatment. In this study, the team shows that TRAIL-induced apoptosis in glioblastoma is inhibited by A20 ubiquitin ligase-mediated ubiquitination. "A20 is highly expressed in glioblastomas and, together with the death receptor 5 and receptor-interacting protein 1, forms a plasma membrane-bound preligand assembly complex under physiologic conditions," the authors write. "Treatment with TRAIL leads to the recruitment of caspase-8 to the plasma membrane-bound preligand assembly complex. … The C-terminal zinc finger domain of the A20 ubiquitin ligase mediates receptor-interacting protein 1 polyubiquitination through lysine-63-linked polyubiquitin chains, which bind to the caspase-8 protease domain and inhibit caspase-8 dimerization, cleavage, and the initiation of TRAIL-induced apoptosis in glioblastoma-derived cell lines and tumor-initiating cells."
Finally in Cancer Discovery this week, researchers in the UK and the US present a study on the OPMCL tumor suppressor and its role in epithelial ovarian cancer. OPMCL is frequently epigenetically inactivated in epithelial ovarian cancers, the team writes. In this study, the team shows that OMPCL functions by regulating a specific set of receptor tyrosine kinases in both ovarian cancer cells and normal ovarian cells. "The OPCML tumor suppressor negatively regulates a specific spectrum of receptor tyrosine kinases in ovarian cancer cells by binding to their extracellular domain and altering trafficking to a nonclathrin, caveolin-1-associated endosomal pathway that results in receptor tyrosine kinase polyubiquitination and proteasomal degradation," the authors write. "Recombinant OPCML domain 1–3 recapitulates this mechanism and may allow for the implementation of an extracellular tumor-suppressor replacement strategy."