Advances in synthetic lethality for cancer therapy: cellular mechanism and clinical translation
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(2020) 13:118
REVIEW
Open Access
Advances in synthetic lethality for cancer therapy: cellular mechanism and clinical translation Win Topatana1,2†, Sarun Juengpanich1,2†, Shijie Li1†, Jiasheng Cao1, Jiahao Hu1, Jiyoung Lee3, Kenneth Suliyanto2, Diana Ma2, Bin Zhang1, Mingyu Chen1,2* and Xiujun Cai1,2,4*
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. Keywords: Cancer therapy, Synthetic lethality, PARP inhibitors, DNA damage response inhibitors, DNA repair
Introduction Cancer is regarded as a complex disease with multiple genetic changes, including oncogenes, tumor suppressors, DNA repair, cancer metabolism, and genetic background, which results in excessive growth, metastasis, and drug resistance [1–3]. The advances in genome sequencing over the past decade demonstrated that tumor-specific genetic alterations and biological changes drive tumor progression, which leads to susceptibilities that could be manipulated to target tumors selectively [4]. Multiple studies have indicated that synthetic lethality is a promising approach that could improve cancer * Correspondence: [email protected]; [email protected] † Win Topatana, Sarun Juengpanich and Shijie Li contributed equally to this work. 1 Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University, Hangzhou 310016, China Full list of author information is available at the end of the article
research and treatment [5, 6]. The concept of synthetic lethality originates from genetic studies in fruit flies which describes the incompatibility between pairs of alleles [7] and indicates the instance where the cooccurrence of multiple gene mutations results in cell death [8]. Unlike conventional targeted therapies, synthetic lethal therapies promote mutation indirect targeting by identifying an alternative synthetic lethal target, ranging from oncogenes to tumor suppressors, DNA repair, cancer metabolism, and even genetic background [9]. Therefore, synthetic lethal in
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