Targeting DNA Damage Response-Mediated Resistance in Non-Small Cell Lung Cancer: From Mechanistic Insights to Drug Development

Abstract

Non-small cell lung cancer (NSCLC) remains a major contributor to cancer-related deaths worldwide, with therapeutic resistance presenting a critical clinical hurdle. The DNA damage response (DDR) constitutes a sophisticated cellular framework that detects, signals, and repairs genetic lesions to preserve genomic stability. While the DDR plays a crucial role in determining the efficacy of radiotherapy and chemotherapy, current research primarily focuses on direct DDR inhibitors, often overlooking the broader regulatory networks that modulate DDR activity. This review aims to comprehensively analyze the upstream and downstream pathways governing DDR in NSCLC, highlighting key molecular regulators, signaling interactions, and potential feedback mechanisms contributing to therapy resistance. By identifying novel regulatory targets and clinically relevant biomarkers, we propose innovative therapeutic strategies to enhance treatment efficacy. Our approach seeks to bridge the gap between DDR dysregulation and precision oncology, offering new perspectives on overcoming resistance and improving patient outcomes in NSCLC.

Keywords: DNA damage response; chemotherapy; drug resistance; homologous recombination; non-homologous end joining; non-small cell lung cancer; radiotherapy; targeted therapy.

Figure 1

DNA damage response signaling pathways. The figure depicts the three DNA repair mechanisms: NHEJ, HR, and NER. NHEJ, active in G1, is initiated by Ku70/Ku80 binding, followed by DNA-PKcs recruitment, ATM activation, and DNA end processing by Artemis and DNA polymerases. Ligation is mediated by the XRCC4-XLF complex and DNA ligase IV. HR, predominant in S/G2, involves end resection by the MRN complex and CtIP, ssDNA stabilization by RPA, and Rad51-mediated strand invasion facilitated by BRCA1/BRCA2. DNA ligase I completes repair, ensuring genomic integrity. NER includes global genomic NER (XPC-RAD23B) and transcription-coupled NER (CSA-CSB). TFIIH unwinds DNA, XPG and ERCC1-XPF excise the lesion, and the gap is filled by DNA polymerases and sealed by DNA ligase I. ATM, Ataxia–Telangiectasia Mutated; BRCA, Breast Cancer; CtIP, C-terminal Binding Protein-Interacting Protein; DDR, DNA Damage Response; DNA-PKcs, DNA-Dependent Protein Kinase Catalytic Subunit; DSB, Double-Strand Break; HR, Homologous Recombination; Ku70/Ku80, Ku Autoantigen 70/80 kDa; MRN, Mre11-Rad50-Nbs1 Complex; NHEJ, Non-Homologous End Joining; Pol, DNA Polymerase; RPA, Replication Protein A; ssDNA, Single-Stranded DNA; XLF, XRCC4-Like Factor; NER, Nucleotide Excision Repair; TFIIH, Transcription Factor IIH; ERCC1, Excision Repair Cross-Complementation Group 1.

Figure 2

Key targets and modulators in the DDR pathway that regulate resistance to radio- and chemotherapy. NSCLC primarily utilizes three DNA repair pathways: Homologous recombination, non-homologous end joining, and nucleotide excision repair. Each pathway is categorized into three functional components: sensors (damage recognition), transducers (signal amplification/kinase activation), and effectors (repair execution). P53 and P21 interact to regulate cell cycle progression and apoptosis. Key regulatory factors and their functions are mapped to their respective components. Red indicates radiotherapy-associated regulators, while blue represents chemotherapy-associated regulators. These factors target core DDR components, influencing NSCLC resistance to radiotherapy and chemotherapy.

Figure 3

Regulatory mechanisms of DDR pathways involved in chemotherapy resistance in NSCLC. (A) Regulation of the HR pathway. ERβ1 enhances chemotherapy sensitivity by promoting G2-M cell cycle arrest via activation of checkpoint kinases CHK1/CHK2 and upregulation of CCNG2. NPAS2 contributes to HR repair and chemoresistance by stabilizing H2AX mRNA, promoting γH2AX accumulation, and increasing phosphorylation of ATM and CHK2. ARRB1 functions as an upstream regulator of NPAS2 to promote its expression. RanBP9 is phosphorylated by ATM under genotoxic stress and translocates to the nucleus, where it stabilizes p21 through USP11-mediated deubiquitination, thereby maintaining cell cycle arrest independently of p53. RanBP9 may also interact with Tip60 or MDM2 to enhance p53 stability and function. (B) Regulation of the NER pathway. In the NER pathway, ERCC1 forms a repair complex with XPF to remove damaged DNA. High ERCC1 expression enhances DNA repair capacity and downregulates NDRG1, contributing to chemoresistance. NSCLC, Non-small Cell Lung Cancer; DDR, DNA Damage Response; HR, Homologous Recombination; NER, Nucleotide Excision Repair; ERβ1, Estrogen Receptor β1; CHK, Checkpoint Kinase; CCNG2, Cyclin G2; NPAS2, Neuronal PAS Domain Protein 2; ARRB1, Arrestin Beta 1; ATM, Ataxia Telangiectasia Mutated; RanBP9, Ran-binding Protein 9; USP11, Ubiquitin-specific Peptidase 11; MDM2, Murine Double Minute 2; ERCC1, Excision Repair Cross-complementation Group 1; NDRG1, N-myc Downstream-regulated Gene 1.