ATR and CDK4/6 inhibition target the growth of methotrexate-resistant choriocarcinoma.

Autor: Georgiou M; Division of Cancer, Department of Surgery and Cancer, Imperial College, London, UK., Ntavelou P; Division of Cancer, Department of Surgery and Cancer, Imperial College, London, UK., Stokes W; Division of Cancer, Department of Surgery and Cancer, Imperial College, London, UK., Roy R; Division of Cancer, Department of Surgery and Cancer, Imperial College, London, UK., Maher GJ; Division of Cancer, Department of Surgery and Cancer, Imperial College, London, UK., Stoilova T; Division of Cancer, Department of Surgery and Cancer, Imperial College, London, UK., Choo JAMY; Division of Cancer, Department of Surgery and Cancer, Imperial College, London, UK., Rakhit CP; MRC Toxicology Unit, University of Cambridge, Cambridge, UK., Martins M; MRC Toxicology Unit, University of Cambridge, Cambridge, UK., Ajuh P; Gemini Biosciences, Liverpool, UK., Horowitz N; Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Brigham and Women's Hospital, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA., Berkowitz RS; Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Brigham and Women's Hospital, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA., Elias K; Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Brigham and Women's Hospital, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA., Seckl MJ; Division of Cancer, Department of Surgery and Cancer, Imperial College, London, UK. m.seckl@imperial.ac.uk., Pardo OE; Division of Cancer, Department of Surgery and Cancer, Imperial College, London, UK. o.pardo@imperial.ac.uk.
Jazyk: angličtina
Zdroj: Oncogene [Oncogene] 2022 Apr; Vol. 41 (18), pp. 2540-2554. Date of Electronic Publication: 2022 Mar 18.
DOI: 10.1038/s41388-022-02251-8
Abstrakt: 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 p16 Ink4a 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.
(© 2022. The Author(s).)
Databáze: MEDLINE
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