Targeting DNA Replication Stress and DNA Double-Strand Break Repair for Optimizing SCLC Treatment
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cancers Review Targeting DNA Replication Stress and DNA Double-Strand Break Repair for Optimizing SCLC Treatment Xing Bian 1,2,3 and Wenchu Lin 1,3,* 1 High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei 230031, Anhui, China 2 University of Science and Technology of China, Hefei 230026, Anhui, China 3 Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, Anhui, China * Correspondence: wenchu@hmfl.ac.cn; Tel.: +86-551-6559-3499 Received: 28 July 2019; Accepted: 27 August 2019; Published: 2 September 2019 Abstract: Small cell lung cancer (SCLC), accounting for about 15% of all cases of lung cancer worldwide, is the most lethal form of lung cancer. Despite an initially high response rate of SCLC to standard treatment, almost all patients are invariably relapsed within one year. Effective therapeutic strategies are urgently needed to improve clinical outcomes. Replication stress is a hallmark of SCLC due to several intrinsic factors. As a consequence, constitutive activation of the replication stress response (RSR) pathway and DNA damage repair system is involved in counteracting this genotoxic stress. Therefore, therapeutic targeting of such RSR and DNA damage repair pathways will be likely to kill SCLC cells preferentially and may be exploited in improving chemotherapeutic efficiency through interfering with DNA replication to exert their functions. Here, we summarize potentially valuable targets involved in the RSR and DNA damage repair pathways, rationales for targeting them in SCLC treatment and ongoing clinical trials, as well as possible predictive biomarkers for patient selection in the management of SCLC. Keywords: small cell lung cancer; replication stress response; DSD repair; therapeutic strategy 1. Introduction Small cell lung cancer (SCLC) is a deadly neuroendocrine tumor that accounts for 15% of all lung cancers [1,2]. SCLC distinguishes clinically from non-small cell lung cancer by its rapid growth and early distant metastases [3]. During the past three decades, the treatment strategy for SCLC is extremely limited, and chemotherapy remains the cornerstone of therapeutic options for SCLC patients [4]. In mammalian cells, the maintenance of genome integrity requires faithful DNA duplication during cell cycle progression [5,6]. To transmit DNA precisely to daughter cells, cells have evolved coordinated and interweaved molecular networks to antagonize the genotoxic stress generated from intrinsic factors and extrinsic causes [7–9]. The defects in the restriction and G1 checkpoints promote the G1-S transition in SCLC cells, leading to premature onset of the S phase [10,11]. Amplification of oncogenes such as MYC family genes and activation of signal transduction cascades like the PI3K/AKT pathway in SCLC also drive rapid cell proliferation [12]. Promotion of S phase entry and demands of unrestrained proliferation often interfere with DNA replication and induce stalled replication fork termed replication stress (RS; Figure1)[ 13]. When the impediments to DNA replication progression cannot be handled in time, the stalled replication forks are susceptible to fork collapse, leading to highly lethal DNA double-strand breaks (DSBs) [14,15]. To prevent the cytotoxicity caused by replication stress, SCLC cells develop a robust DNA damage response (DDR) network including an effective replication stress response (RSR) pathway and a constitutive DNA repair system to tolerate high levels Cancers 2019, 11, 1289; doi:10.3390/cancers11091289 www.mdpi.com/journal/cancers Cancers 2019, 11, 1289 2 of 15 Cancers 2019, 11, x 2 of 14 of RS and to reduce consequent DNA damage [16] (Figure2). 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SCLC Thus, cells a 46 manipulatecoherent understanding replication stress of how response SCLC (RSR)cells manipulate to control DNAreplication replication stress andresponse to fix (RSR) damaged to control DNA 47 mayDNA facilitate replication the developmentand to fix damaged of new therapeutic DNA may strategiesfacilitate andthe circumventdevelopment drug of resistancenew therapeutic in the 48 SCLCstrategies treatment. and circumvent Recent advances drug resi instance transcriptomics in the SCLC and treatment. proteomics Recent have advances identified in transcriptomics a significantly 49 elevatedand proteomics expression have of aidentified number ofa genes,significantly which encodeelevated vital expression proteins of responsible a number for of DNAgenes, damage which 50 responseencode vital in SCLC proteins including responsibleATR ,forCHK1 DN,AWEE1 damage, and responseBRCA1 in[17 SCLC]. In recentincluding years, ATR a, greatCHK1 amount, WEE1, 51 ofand eff ortBRCA1 has been[17]. putIn onrecent the discoveryyears, a great and developmentamount of effort of compounds has been thatput wouldon the exploitdiscovery defects and 52 indevelopment DNA replication of compounds and DNA that repair would to treat exploit cancer defe [cts18]. in However, DNA replication although and the DNA single repair therapeutic to treat 53 agentscancer to[18]. target However, DNA damagealthough response the single have therapeu showntic promising agents to etargetffects, DNA the drug-resistance damage response is often have 54 observedshown promising due to the effects, complexity the drug-resistance of the DNA damage is often response observed network due to [ 19the,20 complexity]. Therefore, of to the expand DNA 55 thedamage therapeutic response effi cacy,network combinations [19,20]. Therefore, of replication to expand stress inducers the therapeutic with other efficacy, therapeutics combinations have been of 56 investigatedreplication stress in preclinical inducers and with clinical other studies therapeutics and have have shown been augmentedinvestigated beneficial in preclinical effects and compared clinical 57 withstudies either and agent have aloneshown [21 augmented–24]. beneficial effects compared with either agent alone [21–24]. 58 59 FigureFigure 1.1. CausesCauses ofof replicationreplication stressstress inin smallsmall cellcell lunglung cancercancer (SCLC)(SCLC) cells.cells. AA numbernumber ofof endogenousendogenous 60 obstaclesobstacles thatthat leadlead toto replicationreplication stressstress inin SCLC,SCLC, includingincluding inactivationinactivation ofof tumortumor suppressorssuppressorsRB1 RB1 andand 61 p53,p53, asas wellwell asas amplificationamplification ofofMYC MYCfamily family genes. genes. RB1RB1 lossloss oror amplificationamplification ofof MYCMYC familyfamily genesgenes 62 promotespromotes G0-G1G0-G1 cell cell cycle cycle entry, entry,p53 p53mutation mutation leads leads to to deficient deficient G1 G1/S/S DNA DNA damage damage checkpoint. checkpoint. Cancers 2019, 11, 1289 3 of 15 Cancers 2019, 11, x 3 of 14 63 64 Figure 2. TheThe DNA DNA damage damage response response network in SCLC cells. ( (AA)) The The roles roles of of the the ATR-CHK1 ATR-CHK1 signaling signaling 65 cascade in response to replication stress, replication protein A (RPA) is firstfirst loaded onto long stretches 66 of single-strand DNA (ssDNA). The ATR was then recruited to the ssDNA sites through interaction 67 with ATRIP. OnceOnce activated,activated, ATR-mediatedATR-mediated activationactivation ofof CHK1CHK1 thenthen transmitstransmits signals of replication 68 stress through multiple mechanisms. ( B) Once persistent persistent replication replication stress cannot be fixed, fixed, replication 69 forks then collapse into double-stranddouble-strand breaks (DSBs). In response to DSBs, SCLC cancer cells activate 70 two major DSB repair pathways: Homologous recombination (HR) and non-homologous end joining 71 (NHEJ). CrucialCrucial proteins proteins involved involved in in the the HR HR repair repair pathway pathway include include BRCA1 BRCA1/2,/2, CHK1 CHK1/2,/2, RAD51, RAD51, ATM, 72 etc.;ATM, the etc.; core the components core components of the NHEJ of the repair NHEJ pathway repair pathway comprise comprise KU70/80, KU70/80, XRCC4, DNA-PK, XRCC4, DNA-PK, etc. Thus, 73 constitutiveetc. Thus, constitutive activation of activation the replication of the stress replication response stress (RSR) response pathway (RSR) and DSB pathway repair systemand DSB is crucialrepair 74 forsystem maintaining is crucial SCLC for maintaining cell survival. SCLC cell survival. 75 Here, we provide an overview of the major sourcessources of replication stress in SCLC cells and the 76 signaling pathwayspathways responsible responsible for for DDR. DDR. We thenWe outlinethen outline the pharmacological the pharmacological approaches approaches to exacerbate to 77 replicationexacerbate stressreplication and to stress target and DNA to target damage DNA repair dama forge SCLC repair treatment, for SCLC with treatment, a specific with focus a specific on RSR 78 andfocus DSB on RSR repair. and Lastly, DSB repair. we discuss Lastly, the we combination discuss the strategiescombination for strategies treatment for and treatment propose theand potential propose 79 strategiesthe potential to furtherstrategies augment to further treatment augment effi treatmentcacy for SCLC. efficacy for SCLC. 80 2. Sources of