WEE1 inhibition by MK1775 as a single-agent therapy inhibits ovarian cancer viability

There is ample evidence for the essential involvement of DNA repair and DNA damage response in the onset of solid malignancies, including ovarian cancer. Indeed, high-penetrance germline mutations in DNA repair genes are important players in familial cancers: BRCA1, BRCA2 mutations or mismatch repair, and polymerase deficiency in colorectal, breast, and ovarian cancers. Recently, some molecular hallmarks (e.g., TP53, KRAS, BRAF, RAD51C/D or PTEN mutations) of ovarian carcinomas were identified. The manuscript overviews the role of DNA repair machinery in ovarian cancer, its risk, prognosis, and therapy outcome. We have attempted to expose molecular hallmarks of ovarian cancer with a focus on DNA repair system and scrutinized genetic, epigenetic, functional, and protein alterations in individual DNA repair pathways (homologous recombination, non-homologous end-joining, DNA mismatch repair, base- and nucleotide-excision repair, and direct repair). We suggest that lack of knowledge particularly in non-homologous end joining repair pathway and the interplay between DNA repair pathways needs to be confronted. The most important genes of the DNA repair system are emphasized and their targeting in ovarian cancer will deserve further attention. The function of those genes, as well as the functional status of the entire DNA repair pathways, should be investigated in detail in the near future.

Section: Chek1imentioning

confidence: 99%

Section: Chek1imentioning

confidence: 99%

See 1 more Smart Citation

DNA Repair and Ovarian Carcinogenesis: Impact on Risk, Prognosis and Therapy Outcome

Tomášová

Čumová

Šeborová

et al. 2020

“…Tumour cells with deficient G1 checkpoint, treated with a WEE-1 inhibitor lose the ability to arrest the cell cycle in response to DNA damage, and enhance apoptosis. Preclinical data have shown potential effectiveness of the treatment in OC xenografts, irrespective of TP53 status and BRCA1 m [201]. However, a phase I dose-finding multi-tumour study did suggest that BRCA m and HRD might be response biomarkers to WEE1 kinase inhibitor monotherapy [202].…”

Section: Treatment Of Ovarian Cancer and Implications Of Brca1/2 Statusmentioning

confidence: 99%

Tailoring Ovarian Cancer Treatment: Implications of BRCA1/2 Mutations

Madariaga

Lheureux

Oza

2019

High grade serous ovarian cancer (HGSOC) is the most common epithelial ovarian cancer, harbouring more than 20% germline or somatic mutations in the tumour suppressor genes BRCA1 and BRCA2. These genes are involved in both DNA damage repair process via homologous recombination (HR) and transcriptional regulation. BRCA mutation confers distinct characteristics, including an increased response to DNA-damaging agents, such us platinum chemotherapy and poly-ADP ribose polymerase inhibitors (PARPi). However, several mechanisms of resistance to these agents have been described, including increased HR capacity through reverse BRCA mutations, non-homologous end-joint (NHEJ) repair alterations and drug efflux pumps. Current treatments of ovarian cancer including surgery, chemotherapy, targeted treatment and maintenance strategies, as well as resistance mechanisms will be reviewed, focusing on future trends with respect to BRCA mutation carriers.

“…Under normal circumstances, factors such as cell cycle disruption and DNA damage result in induction of (intrinsic) apoptosis [6,7,8,9,10]. Indeed, blocking of WEE1 activity with AZD1775 results in apoptosis in solid cancers [11], lymphoma [4], and leukaemia [12,13]. In order to survive intrinsic apoptosis, DLBCL and many other cancers induce upregulation of various anti-apoptotic proteins, leading to apoptosis resistance, resulting in a cellular reliance on anti-apoptotic proteins commonly termed ‘anti-apoptotic dependency’ [14,15].…”

Section: Introductionmentioning

confidence: 99%

WEE1 Inhibition Enhances Anti-Apoptotic Dependency as a Result of Premature Mitotic Entry and DNA Damage

Jong

Langendonk

Reitsma

et al. 2019

Genomically unstable cancers are dependent on specific cell cycle checkpoints to maintain viability and prevent apoptosis. The cell cycle checkpoint protein WEE1 is highly expressed in genomically unstable cancers, including diffuse large B-cell lymphoma (DLBCL). Although WEE1 inhibition effectively induces apoptosis in cancer cells, the effect of WEE1 inhibition on anti-apoptotic dependency is not well understood. We show that inhibition of WEE1 by AZD1775 induces DNA damage and pre-mitotic entry in DLBCL, thereby enhancing dependency on BCL-2 and/or MCL-1. Combining AZD1775 with anti-apoptotic inhibitors such as venetoclax (BCL-2i) or S63845 (MCL-1i) enhanced sensitivity in a cell-specific manner. In addition, we demonstrate that both G2/M cell cycle arrest and DNA damage induction put a similar stress on DLBCL cells, thereby enhancing anti-apoptotic dependency. Therefore, genotoxic or cell cycle disrupting agents combined with specific anti-apoptotic inhibitors may be very effective in genomic unstable cancers such as DLBCL and therefore warrants further clinical evaluation.