Synthetic lethal interaction between WEE1 and PKMYT1 is a target for multiple low-dose treatment of high-grade serous ovarian carcinoma
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Synthetic lethal interaction between WEE1 and PKMYT1 is a target for multiple low-dose treatment of high-grade serous ovarian carcinoma. / Benada, Jan; Bulanova, Daria; Azzoni, Violette; Petrosius, Valdemaras; Ghazanfar, Saba; Wennerberg, Krister; Sørensen, Claus Storgaard.
In: NAR Cancer, Vol. 5, No. 3, zcad029, 2023.Research output: Contribution to journal › Journal article › Research › peer-review
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T1 - Synthetic lethal interaction between WEE1 and PKMYT1 is a target for multiple low-dose treatment of high-grade serous ovarian carcinoma
AU - Benada, Jan
AU - Bulanova, Daria
AU - Azzoni, Violette
AU - Petrosius, Valdemaras
AU - Ghazanfar, Saba
AU - Wennerberg, Krister
AU - Sørensen, Claus Storgaard
N1 - Publisher Copyright: © 2023 The Author(s).
PY - 2023
Y1 - 2023
N2 - 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.
AB - 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.
U2 - 10.1093/narcan/zcad029
DO - 10.1093/narcan/zcad029
M3 - Journal article
C2 - 37325550
AN - SCOPUS:85163201164
VL - 5
JO - NAR Cancer
JF - NAR Cancer
SN - 2632-8674
IS - 3
M1 - zcad029
ER -
ID: 360404438