Comprehensive review of LncRNA-mediated therapeutic resistance in non-small cell lung cancer

Abstract

Long non-coding RNAs (lncRNAs) are emerging as crucial regulators of gene expression through diverse mechanisms, including regulation of protein localization, sequestration of miRNAs, recruitment of chromatin modifiers, and modulation of signaling pathways. Accumulating evidence highlights their pivotal roles in tumor initiation, progression, and the development of therapeutic resistance. In this review, we comprehensively summarized the existing literature to identify lncRNAs associated with treatment responses in non-small cell lung cancer (NSCLC). Specifically, we categorized these lncRNAs based on their mechanisms of action in mediating resistance to chemotherapy, targeted therapy, and radiotherapy. Our analysis revealed that aberrant expression of various lncRNAs contributes to the development, metastasis, and therapeutic resistance in NSCLC, ultimately leading to poor clinical outcomes. By elucidating the intricate mechanisms through which lncRNAs modulate therapeutic responses, this review aims to provide mechanistic insights into the heterogeneous treatment outcomes observed in NSCLC patients and unveil potential therapeutic targets for overcoming drug resistance.

Keywords: Chemotherapy; Long non-coding RNA; Non-small cell lung cancer; Radio therapy; Targeted therapy.

Fig. 1

Mechanisms of lncRNA biogenesis and nuclear localization. Some lncRNAs contain tRNA-like structures at their 3’ ends, which form highly stable triple-helical sequences after RNase P cleavage, thereby increasing stability. Some lncRNAs undergo a series of splicing processes to form special RNAs, including circRNA formed by non-consecutive splicing of introns, circRNA formed by classical intron splicing, sno-lncRNA containing snoRNA components, and lncRNA and miRNA formed by miRNA splicing. Lower splicing efficiency, nuclear retention element, and alternative polyadenylation can all lead to the nuclear localization of lncRNAs. Created in BioRender. Shen, Z. (2024) BioRender.com/v66l891

Fig. 2

LncRNAs Related to DDP Resistance. HOTAIR, SNHG1, XIST, MALAT1, TP53TG1, DLX6-AS1, FGD5-AS1, SNHG14 and UCA1 regulate the expression of downstream proteins or affect the stability of downstream proteins through the ceRNA network. HOTAIR, XIST, MALAT1, UCA1 and SOX-OT directly regulate the phosphorylation or expression of downstream proteins, among which HOTAIR exerts its functions through EZH2. Red arrows represent the promotion of expression or increase in stability, while black arrows represent the inhibition of expression or decrease in stability. Created in BioRender. Shen, Z. (2024) BioRender.com/j45y740

Fig. 3

LncRNAs Related to EGFR-TKIs Resistance. LINC00460, PCAT6, SNHG5, RP11-89K21.1, MALAT1, and CASC9 regulate the expression of downstream proteins or affect the stability of downstream proteins through the ceRNA network. LINC01510, SNHG17, SOX2-OT, and CASC9 directly regulate the expression of downstream proteins, among which SNHG17 and CASC9 exert their functions through EZH2. Red arrows represent the promotion of expression or increase in stability, while black arrows represent the inhibition of expression or decrease in stability. Created in BioRender. Shen, Z. (2024) BioRender.com/r42n471

Fig. 4

LncRNAs Related to Radiotherapy. CYTOR, LINC00461, KCNQ1OT1, HNF1A-AS1, FOXD1-AS1, PTPRG-AS1 regulate the expression of downstream proteins or affect the stability of downstream proteins through the ceRNA network. PCAT1 directly regulate the expression of the downstream protein. Red arrows represent the promotion of expression, while black arrows represent the inhibition of expression or decrease in stability. Created in BioRender. Shen, Z. (2024) BioRender.com/x86i614

Fig. 5

LncRNAs related to the therapeutic effect of NSCLC. XIST, UCA1, HOTAIR, TP53TG1, SNHG1, DLX6-AS1, FGD5-AS1, SNHG14, MALAT1, and SOX2-OT are associated with chemotherapy. CASC9, LINC00460, PCAT6, SNHG5, RP11-89K21.1, SNHG17, LINC01510, MALAT1, and SOX2-OT are associated with targeted therapy. SBF2-AS1, CRNDE, KCNQ1OT1, CYTOR, HNF1A-AS1, LINC00461, PCAT1, PTPRG-AS1, and FOXD-AS1 are related to radiotherapy

Fig. 6

LncRNAs Influence Therapeutic Resistance in NSCLC by Regulating Signaling Pathways. Specifically, RP11-89K21.1 regulates the ROCK pathway, CASC9 and SOX2-OT regulate the ERK pathway, SNHG1 regulates the Wnt/β-catenin pathway, LINC00460, SNHG1, TP53TG1, and SOX2-OT regulate the PI3K-AKT pathway, LINC00460 also regulates the JAK/STAT3 pathway, HNF1A-AS1 regulates the JNK pathway, PCAT1 regulates the cGAS/STING pathway, and UCA1 regulates the NRF2/HO-1 pathway. Created in BioRender. Shen, Z. (2024) BioRender.com/e72m039