Drugging Homologous Recombination: Back to the Future

Abstract

If a person is lucky to live long enough, he/she will also have a significantly increased likelihood of developing a cancer. Cancer is caused by accumulation of gene mutations over time. Genomic instability is one of the two key enabling characteristics of cancer cells [1], first enabling initial tumorigenesis and later drug resistance. Genomic stability is critical to maintain cellular homeostasis and cellular identity. However, cellular DNA is constantly under the attack from both endogenous and exogenous threats, creating lesions. These lesions, particularly the DNA double-strand breaks (DSBs) are lethal to the cells. They must be repaired for the cells to survive and proliferate. There are two major pathways to repair the DSBs in mammalian cells. One is error-free homologous recombination repair (HR) and the other one is error-prone nonhomologous end-joining repair [2]. During HR, a homologous sister chromatin is used as a template to repair the breaks. In nonhomologous end-joining, on the other hand, the broken DNA ends are simply ligated together without a need for a homologous template, often leading to some deletions of the original DNA sequences. It is the HR process that maintains the integrity of our cellular genome. Reversing resistanceWhile genomic instability is a hallmark of cancer cells, the genome cannot be too unstable. After passing a certain intolerable threshold, the cancer cells will die from excessive DSBs or genomic changes. This creates a unique opportunity to develop novel cancer therapies by targeting the HR pathway. The viability of targeting HR repair for anti-cancer therapeutics is supported by the recent US FDA approval of three different PARP inhibitors (olaparib, rucaparib and niraparib) for high-grade serous ovarian cancer (HGSOC). These PARP inhibitors are mostly effective in patients with preexisting somatic or germline BRCA mutations through a process called synthetic lethality [3]. BRCA1 and BRCA2 are two distinct breast and ovarian cancer-associated tumor suppressor genes. They are essential for instigating the HR repair pathway in collaboration with the nuclease MRN (Mre11-Rad50-NBS1) complex [2]. Mutations in BRCA genes result in deficient HR repair activity, a process which cancer cells are particularly reliant on due to high level of replication stress [4]. In the case of HGSOC, carriers of BRCA, which account for only approximately 30% of the patients are more sensitive to existing drugs including platinum salts and PARP inhibitors present significantly better prognosis than noncarriers. Even these BRCA carriers eventually develop resistance to the PARP inhibitors or platinum drugs. Although the mechanisms underlying the resistance are incompletely understood, restoration of HR function is a major cause [5,6]. Therefore, pharmacological strategies to drug the HR pathway can potentially expand the utility of existing PARP inhibitors and platinum drugs by priming the non-BRCA carriers and reversing the resistance mechanisms seen in the clinic with PARP inhibitors and pla...

A Lamin-Binding Ligand Inhibits Homologous Recombination Repair of DNA Double-Strand Breaks

“…This is consistent with our results that normal cells did not produce γ-H2AX signal upon LBL1 treatment. Given the challenges in developing small molecules to directly target HR, 53 extensive efforts are ongoing to identify other druggable regulatory proteins in the HR pathway. 54 , 55 Our finding that the LA–Rad51 interaction is amenable for modulation by small molecules like LBL1 support that the LA–Rad51 axis represents a novel avenue for developing cancer therapeutics that inhibit DSB repair.…”