Figure 6

Proposed model for synthetic lethality between MYC and PRKDC. A) In MYC-driven cancer cells, the overexpression of MYC leads to DNA damage and creates a dependence on DNA repair machinery for cancer cell survival. Double strand breaks (DSBs) induce non-homologous end joining (NHEJ) DNA repair mechanisms to correct for DNA insult. PRKDC is a major player during NHEJ repair, and along with other key components, will restore the impaired DNA allowing for cancer cell viability. In these same cells, exposure to anti-PRKDC drug treatments would ultimately lead to PRKDC inhibition, compromised NHEJ repair and cell death. B) PRKDC has also been implicated in MYC gene regulation. i) In a normal setting, MYC protein is phosphorylated through RAF- and AKT-mediated signaling cascades, resulting in its FBW7-mediated ubiquitination, and subsequent proteasomal degradation. ii) In cancer cells, at the gene level, the inhibition of PRKDC protein decreases MYC expression, potentially through a direct effect or epigenetic mechanism(s). iii) Additionally in cancer cells, PRKDC can phosphorylate AKT, which results in the inhibition of GSK3β and subsequent MYC degradation. Therefore, interference with PRKDC function(s) decreases the stability of MYC protein. This form of genotypic cytotoxicity represents synthetic lethality that selectively targets cancer cells while leaving normal cells unscathed, and offers a potential for wider therapeutic windows for cancer therapies.