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• W4220901373 abstract "Low-risk gestational trophoblastic neoplasia including choriocarcinoma is often effectively treated with Methotrexate (MTX) as a first line therapy. However, MTX resistance (MTX-R) occurs in at least ≈33% of cases. This can sometimes be salvaged with actinomycin-D but often requires more toxic combination chemotherapy. Moreover, additional therapy may be needed and, for high-risk patients, 5% still die from the multidrug-resistant disease. Consequently, new treatments that are less toxic and could reverse MTX-R are needed. Here, we compared the proteome/phosphoproteome of MTX-resistant and sensitive choriocarcinoma cells using quantitative mass-spectrometry to identify therapeutically actionable molecular changes associated with MTX-R. Bioinformatics analysis of the proteomic data identified cell cycle and DNA damage repair as major pathways associated with MTX-R. MTX-R choriocarcinoma cells undergo cell cycle delay in G1 phase that enables them to repair DNA damage more efficiently through non-homologous end joining in an ATR-dependent manner. Increased expression of cyclin-dependent kinase 4 (CDK4) and loss of p16Ink4a in resistant cells suggested that CDK4 inhibition may be a strategy to treat MTX-R choriocarcinoma. Indeed, inhibition of CDK4/6 using genetic silencing or the clinically relevant inhibitor, Palbociclib, induced growth inhibition both in vitro and in an orthotopic in vivo mouse model. Finally, targeting the ATR pathway, genetically or pharmacologically, re-sensitised resistant cells to MTX in vitro and potently prevented the growth of MTX-R tumours in vivo. In short, we identified two novel therapeutic strategies to tackle MTX-R choriocarcinoma that could rapidly be translated into the clinic." @default.
• W4220901373 created "2022-04-03" @default.
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• W4220901373 date "2022-03-18" @default.
• W4220901373 modified "2023-10-18" @default.
• W4220901373 title "ATR and CDK4/6 inhibition target the growth of methotrexate-resistant choriocarcinoma" @default.
• W4220901373 cites W1965511479 @default.
• W4220901373 cites W1966552830 @default.
• W4220901373 cites W1968351802 @default.
• W4220901373 cites W1974861105 @default.
• W4220901373 cites W1975828432 @default.
• W4220901373 cites W1978250212 @default.
• W4220901373 cites W1978518304 @default.
• W4220901373 cites W1979962491 @default.
• W4220901373 cites W1982020575 @default.
• W4220901373 cites W1985825541 @default.
• W4220901373 cites W1991334711 @default.
• W4220901373 cites W1995204735 @default.
• W4220901373 cites W1998418923 @default.
• W4220901373 cites W2005115966 @default.
• W4220901373 cites W2008933923 @default.
• W4220901373 cites W2011076256 @default.
• W4220901373 cites W2013895149 @default.
• W4220901373 cites W2021863432 @default.
• W4220901373 cites W2022787659 @default.
• W4220901373 cites W2024076463 @default.
• W4220901373 cites W2028063483 @default.
• W4220901373 cites W2031211461 @default.
• W4220901373 cites W2035263093 @default.
• W4220901373 cites W2036292773 @default.
• W4220901373 cites W2037679360 @default.
• W4220901373 cites W2039071189 @default.
• W4220901373 cites W2039505540 @default.
• W4220901373 cites W2042044881 @default.
• W4220901373 cites W2045144995 @default.
• W4220901373 cites W2047660841 @default.
• W4220901373 cites W2050200982 @default.
• W4220901373 cites W2062049401 @default.
• W4220901373 cites W2070918875 @default.
• W4220901373 cites W2076526862 @default.
• W4220901373 cites W2082028670 @default.
• W4220901373 cites W2093685655 @default.
• W4220901373 cites W2094065492 @default.
• W4220901373 cites W2096293110 @default.
• W4220901373 cites W2100078246 @default.
• W4220901373 cites W2103451229 @default.
• W4220901373 cites W2107739085 @default.
• W4220901373 cites W2135594199 @default.
• W4220901373 cites W2147139497 @default.
• W4220901373 cites W2147934034 @default.
• W4220901373 cites W2150055220 @default.
• W4220901373 cites W2151252396 @default.
• W4220901373 cites W2155640249 @default.
• W4220901373 cites W2158950505 @default.
• W4220901373 cites W2161097917 @default.
• W4220901373 cites W2162371443 @default.
• W4220901373 cites W2167397744 @default.
• W4220901373 cites W2167752799 @default.
• W4220901373 cites W2169653086 @default.
• W4220901373 cites W2295971206 @default.
• W4220901373 cites W2321716884 @default.
• W4220901373 cites W2526284033 @default.
• W4220901373 cites W2529272995 @default.
• W4220901373 cites W2549441121 @default.
• W4220901373 cites W2564433363 @default.
• W4220901373 cites W2587905891 @default.
• W4220901373 cites W2607044270 @default.
• W4220901373 cites W2613775504 @default.
• W4220901373 cites W2619941405 @default.
• W4220901373 cites W2758489288 @default.
• W4220901373 cites W2769809456 @default.
• W4220901373 cites W2784856005 @default.
• W4220901373 cites W2802998961 @default.
• W4220901373 cites W2885280188 @default.
• W4220901373 cites W2898088739 @default.
• W4220901373 cites W2901534288 @default.
• W4220901373 cites W2902263717 @default.
• W4220901373 cites W2961683572 @default.
• W4220901373 cites W2972906629 @default.
• W4220901373 cites W2980571441 @default.
• W4220901373 cites W2983341247 @default.
• W4220901373 cites W2987975377 @default.
• W4220901373 cites W3007027724 @default.
• W4220901373 cites W3010575887 @default.
• W4220901373 cites W3014482292 @default.

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