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Replication stress for cancer therapy

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  57. Min, W. et al. Poly(ADP-ribose) binding to CHK1 at stalled replication forks is required for S-phase checkpoint activation. Nat. Commun. 4, 2993 (2013).

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  62. Ding, L. et al. PARP inhibition elicits STING-dependent antitumor immunity in BRCA1-deficient ovarian cancer. Cell Rep. 25, 2972–2980.e5 (2018). This is one of the first studies to show that PARPi activate the cGAS–STING pathway to promote antitumour immunity.

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  73. Iyer, S. et al. Genetically defined syngeneic mouse models of ovarian cancer as tools for the discovery of combination immunotherapy. Cancer Discov. 11, 384–407 (2021).

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  79. Moiseeva, T. N., Qian, C., Sugitani, N., Osmanbeyoglu, H. U. & Bakkenist, C. J. WEE1 kinase inhibitor AZD1775 induces CDK1 kinase-dependent origin firing in unperturbed G1- and S-phase cells. Proc. Natl Acad. Sci. USA 116, 23891–23893 (2019).

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  115. Lampert, E. J. et al. Prexasertib, a cell cycle checkpoint kinase 1 inhibitor, in BRCA mutant recurrent high-grade serous ovarian cancer (HGSOC): a proof-of-concept single arm phase II study. J. Clin. Oncol. 38, 6038 (2020).

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  117. Plummer, E. R. et al. A first-in-human phase I/II trial of SRA737 (a Chk1 Inhibitor) in subjects with advanced cancer. J. Clin. Oncol. 37, 3094 (2019).

  118. Miller, W. H. et al. A phase Ib study of oral Chk1 inhibitor LY2880070 as monotherapy in patients with advanced or metastatic cancer. J. Clin. Oncol. 38, 3579 (2020).

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  120. Takebe, N. et al. Safety, antitumor activity, and biomarker analysis in a phase I trial of the once-daily wee1 inhibitor adavosertib (AZD1775) in patients with advanced solid tumors. Clin. Cancer Res. 27, 3834–3844 (2021).

  121. Tolcher, A. et al. Clinical activity of single-agent ZN-c3, an oral WEE1 inhibitor, in a phase 1 dose-escalation trial in patients with advanced solid tumors. Cancer Res. 81 (Suppl. 13), Abstr. CT016 (2021).

  122. Pasic, A. et al. A phase 1b dose-escalation study of ZN-c3, a WEE1 inhibitor, in combination with chemotherapy (CT) in subjects with platinum-resistant or refractory ovarian, peritoneal, or fallopian tube cancer. Cancer Res. 82 (Suppl. 12), Abstr. CT148 (2022).

  123. Lheureux, S. et al. Adavosertib plus gemcitabine for platinum-resistant or platinum-refractory recurrent ovarian cancer: a double-blind, randomised, placebo-controlled, phase 2 trial. Lancet 397, 281–292 (2021). This is one of the two main randomized trials showing activity of the combination of a WEE1i with gemcitabine in platinum-resistant ovarian cancers.

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  125. Fu, S. et al. Phase II trial of the Wee1 inhibitor adavosertib in advanced refractory solid tumors with CCNE1 amplification. Cancer Res. 81 (Suppl. 13), Abstr. 974 (2021).

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  127. Gallo, D. et al. CCNE1 amplification is synthetic lethal with PKMYT1 kinase inhibition. Nature 604, 749–756 (2022). This is the first preclinical study to show the synthetic lethality of PKMYT1 inhibition with CCNE1 amplification.

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  129. Xiao, Y. et al. Identification of preferred chemotherapeutics for combining with a CHK1 Inhibitor. Mol. Cancer Ther. 12, 2285–2295 (2013).

  130. Kreahling, J. M. et al. Wee1 inhibition by MK-1775 leads to tumor inhibition and enhances efficacy of gemcitabine in human sarcomas. PLoS ONE 8, e57523 (2013).

  131. Koh, S. B. et al. Mechanistic distinctions between CHK1 and WEE1 inhibition guide the scheduling of triple therapy with gemcitabine. Cancer Res. 78, 3054–3066 (2018).

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  133. Hirai, H. et al. MK-1775, a small molecule Wee1 inhibitor, enhances antitumor efficacy of various DNA-damaging agents, including 5-fluorouracil. Cancer Biol. Ther. 9, 514–522 (2010).

  134. Fordham, S. E. et al. Inhibition of ATR acutely sensitizes acute myeloid leukemia cells to nucleoside analogs that target ribonucleotide reductase. Blood Adv. 2, 1157–1169 (2018).

  135. Liu, S. et al. Inhibition of ATR potentiates the cytotoxic effect of gemcitabine on pancreatic cancer cells through enhancement of DNA damage and abrogation of ribonucleotide reductase induction by gemcitabine. Oncol. Rep. 37, 3377–3386 (2017).

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  137. Venkatesha, V. A. et al. Sensitization of pancreatic cancer stem cells to gemcitabine by Chk1 inhibition. Neoplasia 14, 519–525 (2012).

  138. Warren, N. J. H. & Eastman, A. Inhibition of checkpoint kinase 1 following gemcitabine-mediated S phase arrest results in CDC7- and CDK2-dependent replication catastrophe. J. Biol. Chem. 294, 1763–1778 (2019).

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