Replication stress for cancer therapy

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Murai, J., Thomas, A., Miettinen, M. & Pommier, Y. Schlafen 11 (SLFN11), a restriction factor for replicative stress induced by DNA-targeting anti-cancer therapies. Pharmacol. Ther. 201, 94–102 (2019).

Mao, S. et al. Resistance to pyrrolobenzodiazepine dimers is associated with SLFN11 downregulation and can be reversed through inhibition of ATR. Mol. Cancer Ther. 20, 541–552 (2021).

Winkler, C. et al. SLFN11 informs on standard of care and novel treatments in a wide range of cancer models. Br. J. Cancer 124, 951–962 (2021).

Shen, J. et al. PARPI triggers the STING-dependent immune response and enhances the therapeutic efficacy of immune checkpoint blockade independent of BRCANEss. Cancer Res. 79, 311–319 (2019).

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.

Schoonen, P. M. et al. Premature mitotic entry induced by ATR inhibition potentiates olaparib inhibition-mediated genomic instability, inflammatory signaling, and cytotoxicity in BRCA2-deficient cancer cells. Mol. Oncol. 13, 2422–2440 (2019).

Mouw, K. W. & Konstantinopoulos, P. A. From checkpoint to checkpoint: DNA damage ATR/Chk1 checkpoint signalling elicits PD-L1 immune checkpoint activation. Br. J. Cancer 118, 933–935 (2018).

Sato, H. et al. DNA double-strand break repair pathway regulates PD-L1 expression in cancer cells. Nat. Commun. 8, 1751 (2017).

Sun, L.-L. et al. Inhibition of ATR downregulates PD-L1 and sensitizes tumor cells to T cell-mediated killing. Am. J. Cancer Res. 8, 1307–1316 (2018).

Wayne, J., Brooks, T., Landras, A. & Massey, A. J. Targeting DNA damage response pathways to activate the STING innate immune signaling pathway in human cancer cells. FEBS J. 288, 4507–4540 (2021).

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Sen, T. et al. Targeting DNA damage response promotes antitumor immunity through STING-mediated T-cell activation in small cell lung cancer. Cancer Discov. 9, 646–661 (2019).

Sen, T. et al. Combination treatment of the oral CHK1 inhibitor, SRA737, and low-dose gemcitabine enhances the effect of programmed death ligand 1 blockade by modulating the immune microenvironment in SCLC. J. Thorac. Oncol. 14, 2152–2163 (2019).

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Zhang, S. et al. Genetically defined, syngeneic organoid platform for developing combination therapies for ovarian cancer. Cancer Discov. 11, 362–383 (2021).

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Tang, Z. et al. ATR inhibition induces CDK1–SPOP signaling and enhances anti-PD-L1 cytotoxicity in prostate cancer. Clin. Cancer Res. 27, 4898–4909 (2021).

Pilger, D., Seymour, L. W. & Jackson, S. P. Interfaces between cellular responses to DNA damage and cancer immunotherapy. Genes. Dev. 35, 602–618 (2021).

Sheng, H. et al. ATR inhibitor AZD6738 enhances the antitumor activity of radiotherapy and immune checkpoint inhibitors by potentiating the tumor immune microenvironment in hepatocellular carcinoma. J. Immunother. Cancer 8, e000340 (2020).

Young, L. A. et al. Differential activity of ATR and Wee1 inhibitors in a highly sensitive subpopulation of DLBCL linked to replication stress. Cancer Res. 79, 3762–3775 (2019).

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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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Kausar, T. et al. Sensitization of pancreatic cancers to gemcitabine chemoradiation by WEE1 kinase inhibition depends on homologous recombination repair. Neoplasia 17, 757–766 (2015).

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Hirai, H. et al. Small-molecule inhibition of Wee1 kinase by MK-1775 selectively sensitizes p53-deficient tumor cells to DNA-damaging agents. Mol. Cancer Ther. 8, 2992–3000 (2009).

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Hong, D. S. et al. Evaluation of prexasertib, a checkpoint kinase 1 inhibitor, in a phase Ib study of patients with squamous cell carcinoma. Clin. Cancer Res. 24, 3263–3272 (2018).

Lee, J. M. et al. Prexasertib, a cell cycle checkpoint kinase 1 and 2 inhibitor, in BRCA wild-type recurrent high-grade serous ovarian cancer: a first-in-class proof-of-concept phase 2 study. Lancet Oncol. 19, 207–215 (2018). This clinical study is the first to show the activity of a CHK1 inhibitor to treat HGSOC.

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).

Ditano, J. P. & Eastman, A. comparative activity and off-target effects in cells of the CHK1 inhibitors MK-8776, SRA737, and LY2606368. ACS Pharmacol. Transl. Sci. 4, 730–743 (2021).

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).

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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).

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).

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).

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.

Meric-Bernstam, F. et al. Safety and clinical activity of single-agent ZN-c3, an oral WEE1 inhibitor, in a phase 1 trial in subjects with recurrent or advanced uterine serous carcinoma (USC). Cancer Res. 82 (Suppl. 12), Abstr. CT029 (2022).

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).

Ghelli Luserna Di Rorà, A., Cerchione, C., Martinelli, G. & Simonetti, G. A WEE1 family business: regulation of mitosis, cancer progression, and therapeutic target. J. Hematol. Oncol. 13, 126 (2020).

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.

Meng, X. et al. AZD1775 increases sensitivity to olaparib and gemcitabine in cancer cells with p53 mutations. Cancers 10, 149 (2018).

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

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).

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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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).

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).

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).

Wallez, Y. et al. The ATR inhibitor AZD6738 synergizes with gemcitabine in vitro and in vivo to induce pancreatic ductal adenocarcinoma regression. Mol. Cancer Ther. 17, 1670–1682 (2018).

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

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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Leijen, S. et al. Phase I study evaluating WEE1 inhibitor AZD1775 as monotherapy and in combination with gemcitabine, cisplatin, or carboplatin in patients with advanced solid tumors. J. Clin. Oncol. 34, 4371–4380 (2016). This was one of the first clinical studies showing the safety and activity of WEE inhibition in patients with solid tumors.

Cuneo, K. C. et al. Dose escalation trial of the WEE1 inhibitor adavosertib (AZD1775) in combination with gemcitabine and radiation for patients with locally advanced pancreatic cancer. J. Clin. Oncol. 37, 2643–2650 (2019).

Banerji, U. et al. A phase I/II first-in-human trial of oral SRA737 (a Chk1 inhibitor) given in combination with low-dose gemcitabine in subjects with advanced cancer. J. Clin. Oncol. 37, 3095 (2019).

Hong, D. S. et al. Preclinical evaluation and phase Ib study of prexasertib, a CHK1 inhibitor, and samotolisib (LY3023414), a dual PI3K/mTOR inhibitor. Clin. Cancer Res. 27, 1864–1874 (2021).

Konstantinopoulos, P. A. et al. Berzosertib plus gemcitabine versus gemcitabine alone in platinum-resistant high-grade serous ovarian cancer: a multicentre, open-label, randomised, phase 2 trial. Lancet Oncol. 21, 957–968 (2020). This is the first randomized study to show the activity of the ATRi berzosertib in patients with platinum-resistant HGSOC.

Leijen, S. et al. Phase II study of WEE1 inhibitor AZD1775 plus carboplatin in patients with TP53-mutated ovarian cancer refractory or resistant to first-line therapy within 3 months. J. Clin. Oncol. 34, 4354–4361 (2016).

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Huntoon, C. J. et al. ATR inhibition broadly sensitizes ovarian cancer cells to chemotherapy independent of BRCA status. Cancer Res. 73, 3683–3691 (2013).

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