The synthetic lethality of targeting cell cycle checkpoints and PARPs in cancer treatment

Abstract

Continuous cell division is a hallmark of cancer, and the underlying mechanism is tumor genomics instability. Cell cycle checkpoints are critical for enabling an orderly cell cycle and maintaining genome stability during cell division. Based on their distinct functions in cell cycle control, cell cycle checkpoints are classified into two groups: DNA damage checkpoints and DNA replication stress checkpoints. The DNA damage checkpoints (ATM-CHK2-p53) primarily monitor genetic errors and arrest cell cycle progression to facilitate DNA repair. Unfortunately, genes involved in DNA damage checkpoints are frequently mutated in human malignancies. In contrast, genes associated with DNA replication stress checkpoints (ATR-CHK1-WEE1) are rarely mutated in tumors, and cancer cells are highly dependent on these genes to prevent replication catastrophe and secure genome integrity. At present, poly (ADP-ribose) polymerase inhibitors (PARPi) operate through “synthetic lethality” mechanism with mutant DNA repair pathways genes in cancer cells. However, an increasing number of patients are acquiring PARP inhibitor resistance after prolonged treatment. Recent work suggests that a combination therapy of targeting cell cycle checkpoints and PARPs act synergistically to increase the number of DNA errors, compromise the DNA repair machinery, and disrupt the cell cycle, thereby increasing the death rate of cancer cells with DNA repair deficiency or PARP inhibitor resistance. We highlight a combinational strategy involving PARP inhibitors and inhibition of two major cell cycle checkpoint pathways, ATM-CHK2-TP53 and ATR-CHK1-WEE1. The biological functions, resistance mechanisms against PARP inhibitors, advances in preclinical research, and clinical trials are also reviewed.

Chaetoglobosin E inhibits tumor growth and promotes the anti-tumor efficacy of cytotoxic drugs in esophageal squamous cell carcinoma by targeting PLK1

“…Several previous studies have confirmed that the cell cycle is a crucial factor affecting tumor growth ( 20 , 21 ). Our results showed that chaetoglobosin E induced G2/M phase arrest of KYSE-30 cells, followed by the down-regulation of cyclinB1, CDC2, and p-CDC2, and the up-regulation of p21.…”

Molecular subtypes based on centrosome-related genes can predict prognosis and therapeutic responsiveness in patients with low-grade gliomas

“…Smc4, a core subunit of condensing, has been reported to be associated with a variety of tumors, such as hepatocellular carcinoma ( 47 ), prostate cancer ( 48 ), and lung adenocarcinoma ( 49 ), and activated TGFβ/Smad signaling has been reported to promote the aggressive phenotype of glioma ( 50 ). Targeting poly (ADP-ribose) polymerase and cell cycle checkpoints, ATM-CHK2-TP53 and ATR-CHK1-WEE1, can benefit tumor therapy through a synthetic lethality mechanism ( 51 ). Moreover, WEE1 inhibition can boost anti-tumor immunity by activating ERV and the dsRNA pathway and strengthen sensitivity to immune checkpoint blockade ( 52 ).…”

PARP inhibitor and immune checkpoint inhibitor may have synergism efficacy in gallbladder cancer

“…PARP inhibitors induce synthetic lethality in cancer cells with defects in DNA repair, particularly those with BRCA mutations. This is achieved by inhibiting an alternative repair mechanism, which leads to the accumulation of unrepaired DNA damage and subsequent cell death 33,34 . Recent studies have highlighted the signi cant effects of PARP inhibitors (PARPi) on shaping the tumor microenvironment, which leads to an enhanced antitumor immune response.…”