Targeting the replication gap vulnerability in cancer
Figure Legend: Replication gaps as the true vulnerability in BRCA deficient cancer. The molecular basis for the sensitivity of cells with mutations in BRCA proteins to drugs such as PARP inhibitors (PARPi) is thought to stem from the conversion of single-strand DNA breaks to double-strand breaks during DNA replication (current dogma). This concept is supported by the role of the BRCA proteins in fixing DNA double stranded breaks (DSBs) Rather than pausing or stopping at a road block, disparate DNA lesions/roadblocks could similarly trigger re-priming leaving gaps in the wake of replication that we propose is the sensitizing lesion (Alternative Framework). This concept is supported by the role of the BRCA proteins in preventing and fixing single stranded DNA breaks/gaps. If gaps are the true vulnerability, gap making drugs should selectively kill BRCA deficient cancer cells, lets start testing!
As described above, if gaps are the true vulnerability in cancer, then drugs making more gaps should be ideal for uniquely targeting cancer cells. To test this hypothesis, we are addressing whether drugs enhancing lagging strand gaps will sensitize BRCA deficient cancer cells that have an inherent lagging strand synthesis defect. In addition, we are testing the efficacy of targeting gap suppression and repair pathways that operate during or in post-replication. For example, we found that the pathway of translesion synthesis (TLS) is uniquely active in several cancers that have rewired their replisome to engage TLS as a mechanism to suppress gaps and limit cell death. Therefore, TLS is a selective target to kill cancer cells and not harm non-cancer cells (Nayak et al., Science Advances 2020). To systematically address the potential of drug synergy, we are developing a rapid gap detection assay.