Synthetic lethal interaction between WEE1 and PKMYT1 is a target for multiple low-dose treatment of high-grade serous ovarian carcinoma

Abstract

Ovarian cancer is driven by genetic alterations that necessitate protective DNA damage and replication stress responses through cell cycle control and genome maintenance. This creates specific vulnerabilities that may be exploited therapeutically. WEE1 kinase is a key cell cycle control kinase, and it has emerged as a promising cancer therapy target. However, adverse effects have limited its clinical progress, especially when tested in combination with chemotherapies. A strong genetic interaction between WEE1 and PKMYT1 led us to hypothesize that a multiple low-dose approach utilizing joint WEE1 and PKMYT1 inhibition would allow exploitation of the synthetic lethality. We found that the combination of WEE1 and PKMYT1 inhibition exhibited synergistic effects in eradicating ovarian cancer cells and organoid models at a low dose. The WEE1 and PKMYT1 inhibition synergistically promoted CDK activation. Furthermore, the combined treatment exacerbated DNA replication stress and replication catastrophe, leading to increase of the genomic instability and inflammatory STAT1 signalling activation. These findings suggest a new multiple low-dose approach to harness the potency of WEE1 inhibition through the synthetic lethal interaction with PKMYT1 that may contribute to the development of new treatments for ovarian cancer.

Targeting CCNE1 amplified ovarian and endometrial cancers by combined inhibition of PKMYT1 and ATR

“…Taken together this study indicates that CCNE1 amplified OVCA and EMCA cells are specifically vulnerable to CDK1 activation and strategies to increase CDK1 activation offer an attractive therapeutic avenue for this unmet need in the clinic. Preclinically, other combinations targeting CCNE1 overexpression include CDK2 inhibition (e.g dinaciclib) with AKT inhibition, CDK2/9 and PIK3CA inhibition, and WEE1 with PKMYT1 inhibition [44][45][46][47] .…”

Key Proteins of Replication Stress Response and Cell Cycle Control as Cancer Therapy Targets

“…Additionally, PKMYT1 and WEE1 inhibition synthetically eradicates cancers with high levels of RS such as glioma [205] and HGSOC, relatively sparing normal tissues or cancers with lower levels of RS [206]. As WEE1i are hindered by toxicity, the authors consider such combinations more selective for therapy.…”

BRCAness, DNA gaps, and gain and loss of PARP inhibitor–induced synthetic lethality

“…The tyrosine kinase WEE1 inhibits both CDK1 and CDK2 by phosphorylating the tyrosine 15 of these two kinases ( 99 ). WEE1 inhibitor (WEE1i) induces hyperactivation of CDK1/2 and overrides the G 2 /M DNA damage checkpoint, leading to excessive replication origin firing, replication catastrophe in S phase, and mitotic catastrophe in mitosis ( 99 , 100 ). The combination of WEE1i and PARPi overcomes PARPi resistance in breast and ovarian cancer models ( 101 ).…”