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.
Highlights
Small cell lung cancer (SCLC) is a deadly neuroendocrine tumor that accounts for 15% of all lung cancers [1,2]
Poly (ADP-Ribose) Polymerase (PARP) inhibitor veliparib has been evaluated in combination with cisplatin or etoposide in extensive-stage SCLC, and this combination strategy has shown improved efficacy compared to the standard of care [23,24]
It has been increasingly apparent that exceptional high genome instability in SCLC is likely due to high levels of replication stress (Figure 1)
Summary
Small cell lung cancer (SCLC) is a deadly neuroendocrine tumor that accounts for 15% of all lung cancers [1,2]. To expand shown promising effects, the drug-resistance is often observed due to the complexity of the DNA the therapeutic efficacy, combinations of replication stress inducers with other therapeutics have been damage response network [19,20]. Cancer cells often rewire metabolic flux to generate metabolites as either a direct or indirect consequence of activation of oncogenic pathways such as PI3K/AKT, which meet the demands for sustained proliferation and many other fundamental cellular functions in SCLC cells [32]. As metabolites such as deoxynucleoside triphosphates (dNTPs) are the basic units for DNA replication, any disturbance of nucleotide anabolism may interfere with. Chromatin modifiers affect the expression of DNA-replicative enzymes by transcriptional regulation
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