Targeting DNA Damage Repair and Immune Checkpoint Proteins for Optimizing the Treatment of Endometrial Cancer

Abstract

The dependence of cancer cells on the DNA damage response (DDR) pathway for the repair of endogenous- or exogenous-factor-induced DNA damage has been extensively studied in various cancer types, including endometrial cancer (EC). Targeting one or more DNA damage repair protein with small molecules has shown encouraging treatment efficacy in preclinical and clinical models. However, the genes coding for DDR factors are rarely mutated in EC, limiting the utility of DDR inhibitors in this disease. In the current review, we recapitulate the functional role of the DNA repair system in the development and progression of cancer. Importantly, we discuss strategies that target DDR proteins, including PARP, CHK1 and WEE1, as monotherapies or in combination with cytotoxic agents in the treatment of EC and highlight the compounds currently being evaluated for their efficacy in EC in clinic. Recent studies indicate that the application of DNA damage agents in cancer cells leads to the activation of innate and adaptive immune responses; targeting immune checkpoint proteins could overcome the immune suppressive environment in tumors. We further summarize recently revolutionized immunotherapies that have been completed or are now being evaluated for their efficacy in advanced EC and propose future directions for the development of DDR-based cancer therapeutics in the treatment of EC.

Keywords: DNA damage repair; PARP; endometrial cancer; immunotherapy.

Figure 1

The repair of single-strand DNA breaks via BER. (Left: short-patch BER) The damaged bases are removed by DNA glycosylase, then the remaining abasic site (Ab) is cleaved by an apurinic/apyrimidinic endonuclease, leaving a 1-bp DNA gap. The 5′ abasic sugar is removed by DNA polymerase β (POLβ), which inserts a new nucleotide into the DNA gap. Finally, the nick is ligated by DNA ligase 3 (LIG3). (Right: long-patch BER) In long-patch repair, about 2–30 nucleotides are replaced. Polyβ induces the formation of an extended gap, then the gap displaces the 5′-terminus to create a flap that is excised by FEN1. Finally, the DNA ligase 1 ligates 5′ and 3′ nicks.

Figure 2

DNA double-strand breaks by homologous recombination. The first step for homologous recombination includes the initiation of end resection, which is mediated by the CtIP—MRN complex (short-patch) or the EXO1/DNA2 (long-patch) nuclease. DNA end resection leads to the generation of 3′ssDNA overhangs, which are bound by replication protein A. Then, BRCA2 exchanges replication protein A on the DNA ends to promote the formation of RAD51 nucleoprotein filaments. The RAD51–ssDNA nucleoprotein filaments mediates homology search by invasion of template dsDNA. Furthermore, the RAD51–ssDNA nucleoprotein filaments form a synaptic complex that contains a three-stranded DNA helix intermediate. In this process, DNA polymerase δ (Pol δ) plays an important role in the synthesis of nascent strands.

Figure 3

Non-homologous end joining repair mediates the repair of DNA double-strand breaks. DNA double-strand breaks can be repaired via c-NHEJ (left), A-NHEJ (middle), and single-strand annealing (SSA) (right). 53BP1 is a positive regulator of c-NHEJ, and the process usually requires 4-bp microhomology. A-NHEJ, also called microhomology-mediated end joining, requires 2–20 bp microhomology for break repair. PARP1 and Pol θ are important for A-NHEJ. Higher levels of resection can further promote SSA repair pathway, which requires >25 bp microhomology. BLM and EXO1 account for additional resections in SSA. Replication protein A binds and stabilizes ssDNA and promotes SSA. RAD52-mediated annealing of a homologous sequence is important for SSA. ERCC1/XPF cuts the remaining 3′ nonhomologous ssDNA prior to ligation by DNA LIG1.

Figure 4

DNA damage repair blockade stimulates innate antitumor immunity via the cGAS-STING pathway. Upon DNA damage, DNA repair proteins are recruited to DNA damage sites for DNA repair. Inhibition of components of the repair pathway leads to cell-cycle checkpoint abrogation and inappropriate mitotic entry, and ultimately, induces mitotic catastrophe. In addition to being cytotoxic, DDR inhibitors exhibit antitumor immunity. PARPi, ATRi, or CHK1i-induced DSBs generate cytosolic dsDNA fragments, which activate the cGAS-STING innate immune pathway to initiate the IFN-γ response. This innate immune response upregulates chemokines, such like CCL5 or CXCL10, to enhance T cell recruitment. Moreover, PD-L1 expression is upregulated by IFN-γ that may lead to T cell exhaustion, an effect that can be abrogated using PD-1 or PD-L1 antibodies.