Advances in Synthetic Lethality for Cancer Therapy: Cellular Mechanism and Clinical Translation

Overview

Journal J Hematol Oncol

Publisher Biomed Central

Specialties Hematology
Oncology

Date 2020 Sep 5

PMID 32883316

Citations 79

Authors

Win Topatana

Sarun Juengpanich

Shijie Li

Jiasheng Cao

Jiahao Hu

Jiyoung Lee

Kenneth Suliyanto

Diana Ma

Bin Zhang

Mingyu Chen

Xiujun Cai

Affiliations

Soon will be listed here.

Abstract

Synthetic lethality is a lethal phenomenon in which the occurrence of a single genetic event is tolerable for cell survival, whereas the co-occurrence of multiple genetic events results in cell death. The main obstacle for synthetic lethality lies in the tumor biology heterogeneity and complexity, the inadequate understanding of synthetic lethal interactions, drug resistance, and the challenges regarding screening and clinical translation. Recently, DNA damage response inhibitors are being tested in various trials with promising results. This review will describe the current challenges, development, and opportunities for synthetic lethality in cancer therapy. The characterization of potential synthetic lethal interactions and novel technologies to develop a more effective targeted drug for cancer patients will be explored. Furthermore, this review will discuss the clinical development and drug resistance mechanisms of synthetic lethality in cancer therapy. The ultimate goal of this review is to guide clinicians at selecting patients that will receive the maximum benefits of DNA damage response inhibitors for cancer therapy.

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References

Kantidze O, Velichko A, Luzhin A, Petrova N, Razin S . Synthetically Lethal Interactions of ATM, ATR, and DNA-PKcs. Trends Cancer. 2018; 4(11):755-768. DOI: 10.1016/j.trecan.2018.09.007. View

Huang T, Fowler F, Chen C, Shen Z, Sleckman B, Tyler J . The Histone Chaperones ASF1 and CAF-1 Promote MMS22L-TONSL-Mediated Rad51 Loading onto ssDNA during Homologous Recombination in Human Cells. Mol Cell. 2018; 69(5):879-892.e5. PMC: 5843376. DOI: 10.1016/j.molcel.2018.01.031. View

Ryan C, Bajrami I, Lord C . Synthetic Lethality and Cancer - Penetrance as the Major Barrier. Trends Cancer. 2018; 4(10):671-683. DOI: 10.1016/j.trecan.2018.08.003. View

Dietlein F, Thelen L, Jokic M, Jachimowicz R, Ivan L, Knittel G . A functional cancer genomics screen identifies a druggable synthetic lethal interaction between MSH3 and PRKDC. Cancer Discov. 2014; 4(5):592-605. DOI: 10.1158/2159-8290.CD-13-0907. View

Baluapuri A, Wolf E, Eilers M . Target gene-independent functions of MYC oncoproteins. Nat Rev Mol Cell Biol. 2020; 21(5):255-267. PMC: 7611238. DOI: 10.1038/s41580-020-0215-2. View

Adames N, Gallegos J, Peccoud J . Yeast genetic interaction screens in the age of CRISPR/Cas. Curr Genet. 2018; 65(2):307-327. PMC: 6420903. DOI: 10.1007/s00294-018-0887-8. View

George A, Kaye S, Banerjee S . Delivering widespread BRCA testing and PARP inhibition to patients with ovarian cancer. Nat Rev Clin Oncol. 2016; 14(5):284-296. DOI: 10.1038/nrclinonc.2016.191. View

Du C, Qi Y, Zhang Y, Wang Y, Zhao X, Min H . Epidermal Growth Factor Receptor-Targeting Peptide Nanoparticles Simultaneously Deliver Gemcitabine and Olaparib To Treat Pancreatic Cancer with Breast Cancer 2 ( BRCA2) Mutation. ACS Nano. 2018; 12(11):10785-10796. DOI: 10.1021/acsnano.8b01573. View

Hartwell L, Szankasi P, Roberts C, Murray A, Friend S . Integrating genetic approaches into the discovery of anticancer drugs. Science. 1997; 278(5340):1064-8. DOI: 10.1126/science.278.5340.1064. View

10.

Hong D, Infante J, Janku F, Jones S, Nguyen L, Burris H . Phase I Study of LY2606368, a Checkpoint Kinase 1 Inhibitor, in Patients With Advanced Cancer. J Clin Oncol. 2016; 34(15):1764-71. PMC: 5321045. DOI: 10.1200/JCO.2015.64.5788. View

11.

Rogers R, Walton M, Cherry D, Collins I, Clarke P, Garrett M . CHK1 Inhibition Is Synthetically Lethal with Loss of B-Family DNA Polymerase Function in Human Lung and Colorectal Cancer Cells. Cancer Res. 2020; 80(8):1735-1747. PMC: 7611445. DOI: 10.1158/0008-5472.CAN-19-1372. View

12.

Ebeid K, Meng X, Thiel K, Do A, Geary S, Morris A . Synthetically lethal nanoparticles for treatment of endometrial cancer. Nat Nanotechnol. 2017; 13(1):72-81. PMC: 5762267. DOI: 10.1038/s41565-017-0009-7. View

13.

Kruiswijk F, Labuschagne C, Vousden K . p53 in survival, death and metabolic health: a lifeguard with a licence to kill. Nat Rev Mol Cell Biol. 2015; 16(7):393-405. DOI: 10.1038/nrm4007. View

14.

Pavlova N, Thompson C . The Emerging Hallmarks of Cancer Metabolism. Cell Metab. 2016; 23(1):27-47. PMC: 4715268. DOI: 10.1016/j.cmet.2015.12.006. View

15.

Li A, Yi M, Qin S, Chu Q, Luo S, Wu K . Prospects for combining immune checkpoint blockade with PARP inhibition. J Hematol Oncol. 2019; 12(1):98. PMC: 6744711. DOI: 10.1186/s13045-019-0784-8. View

16.

ONeil N, Bailey M, Hieter P . Synthetic lethality and cancer. Nat Rev Genet. 2017; 18(10):613-623. DOI: 10.1038/nrg.2017.47. View

17.

Wang J, Jiang J, Chen H, Wang L, Guo H, Yang L . FDA-approved drug screen identifies proteasome as a synthetic lethal target in MYC-driven neuroblastoma. Oncogene. 2019; 38(41):6737-6751. DOI: 10.1038/s41388-019-0912-5. View

18.

Lee S, Segura-Bayona S, Villamor-Paya M, Saredi G, Todd M, Stephan-Otto Attolini C . Tousled-like kinases stabilize replication forks and show synthetic lethality with checkpoint and PARP inhibitors. Sci Adv. 2018; 4(8):eaat4985. PMC: 6082654. DOI: 10.1126/sciadv.aat4985. View

19.

Brown C, Lain S, Verma C, Fersht A, Lane D . Awakening guardian angels: drugging the p53 pathway. Nat Rev Cancer. 2009; 9(12):862-73. DOI: 10.1038/nrc2763. View

20.

Luo M, He H, Kelley M, Georgiadis M . Redox regulation of DNA repair: implications for human health and cancer therapeutic development. Antioxid Redox Signal. 2009; 12(11):1247-69. PMC: 2864659. DOI: 10.1089/ars.2009.2698. View