Perspectives on Acquired Resistance to PD-1 Axis Inhibitors in Patients with Non–Small Cell Lung Cancer

Tseng, Diane; Padda, Sukhmani K.; Wakelee, Heather A.

doi:10.1016/j.jtho.2018.04.008

Cited by 5 publications

(3 citation statements)

References 21 publications

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“…Anti-PD-1 immunotherapy has led to an effective antitumor response rate in multiple advanced cancers, including NSCLC [43, 44]. However, more than one-half of NSCLC patients do not show a long-term response to anti-PD-1-based immunotherapy [45, 46]. Recent studies have shown that dysregulation of chemokine receptor expression is one of the critical intrinsic tumor-promoting regulators in cancers, as they even promote immune system evasion [30, 47–49].…”

Section: Discussionmentioning

confidence: 99%

Circular RNA circFGFR1 promotes progression and anti-PD-1 resistance by sponging miR-381-3p in non-small cell lung cancer cells

et al. 2019

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BackgroundImmune system evasion, distance tumor metastases, and increased cell proliferation are the main reasons for the progression of non-small cell lung cancer (NSCLC) and the death of NSCLC patients. Dysregulation of circular RNAs plays a critical role in the progression of NSCLC; therefore, further understanding the biological mechanisms of abnormally expressed circRNAs is critical to discovering novel, promising therapeutic targets for NSCLC treatment.MethodsThe expression of circular RNA fibroblast growth factor receptor 1 (circFGFR1) in NSCLC tissues, paired nontumor tissues, and cell lines was detected by RT-qPCR. The role of circFGFR1 in NSCLC progression was assessed both in vitro by CCK-8, clonal formation, wound healing, and Matrigel Transwell assays and in vivo by a subcutaneous tumor mouse assay. In vivo circRNA precipitation, RNA immunoprecipitation, and luciferase reporter assays were performed to explore the interaction between circFGFR1 and miR-381-3p.ResultsHere, we report that circFGFR1 is upregulated in NSCLC tissues, and circFGFR1 expression is associated with deleterious clinicopathological characteristics and poor prognoses for NSCLC patients. Forced circFGFR1 expression promoted the migration, invasion, proliferation, and immune evasion of NSCLC cells. Mechanistically, circFGFR1 could directly interact with miR-381-3p and subsequently act as a miRNA sponge to upregulate the expression of the miR-381-3p target gene C-X-C motif chemokine receptor 4 (CXCR4), which promoted NSCLC progression and resistance to anti-programmed cell death 1 (PD-1)- based therapy.ConclusionTaken together, our results suggest the critical role of circFGFR1 in the proliferation, migration, invasion, and immune evasion abilities of NSCLC cells and provide a new perspective on circRNAs during NSCLC progression.

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Section: Discussionmentioning

confidence: 99%

Circular RNA circFGFR1 promotes progression and anti-PD-1 resistance by sponging miR-381-3p in non-small cell lung cancer cells

et al. 2019

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“…27 Immunotherapies such as PD-1 and PD-L1 antibodies (eg, nivolumab and atezolizumab) are also effective for the treatment of some NSCLC patients regardless of the subtype. 28 While targeted and immunotherapies are generally less toxic and personalized for particular patients, some patients do exhibit primary or acquires resistance 29,30 or show severe adverse effects such as diarrhea and pneumonitis. [31][32][33] In addition, targeted therapies have the greatest response rate for patients with the indicated mutation, therefore, due to the high heterogeneity of mutations within NSCLC, targeted therapies may not work in every patient.…”

Section: Molecular Medicine or Pharmacotherapy Spans From Chemotherapymentioning

confidence: 99%

MicroRNAs in non‐small cell lung cancer: Gene regulation, impact on cancer cellular processes, and therapeutic potential

Petrek

2019

Pharmacology Res & Perspec

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Lung cancer remains the most lethal cancer among men and women in the United States and worldwide. The majority of lung cancer cases are classified as non‐small cell lung cancer (NSCLC). Developing new therapeutics on the basis of better understanding of NSCLC biology is critical to improve the treatment of NSCLC. MicroRNAs (miRNAs or miRs) are a superfamily of genome‐derived, small noncoding RNAs that govern posttranscriptional gene expression in cells. Functional miRNAs are commonly dysregulated in NSCLC, caused by genomic deletion, methylation, or altered processing, which may lead to the changes of many cancer‐related pathways and processes, such as growth and death signaling, metabolism, angiogenesis, cell cycle, and epithelial to mesenchymal transition, as well as sensitivity to current therapies. With the understanding of miRNA biology in NSCLC, there are growing interests in developing new therapeutic strategies, namely restoration of tumor suppressive miRNAs and inhibition of tumor promotive miRNAs, to combat against NSCLC. In this article, we provide an overview on the molecular features of NSCLC and current treatment options with a focus on pharmacotherapy and personalized medicine. By illustrating the roles of miRNAs in the control of NSCLC tumorigenesis and progression, we highlight the latest efforts in assessing miRNA‐based therapies in animal models and discuss some critical challenges in developing RNA therapeutics.

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“…The emergence of anti-PD-1 immunotherapy for the treatment of non-small cell lung cancer (NSCLC) has effectively improved the prognosis of the patients [2]. However, anti-PD-1-based immunotherapy only bene ts 30-40% of the NSCLC patients, and many of the patients will generate acquired resistance during the process of the therapy [3,4]. Lung adenocarcinoma (LUAD) is the most histopathological subtype of NSCLC [5].…”

Section: Introductionmentioning

confidence: 99%

CircRUNX1 Drives Immune Evasion and anti-PD1 Immunotherapy Resistance in Lung Adenocarcinoma by the miR-4739/PCSK9/MHC I Axis

Zhang

et al. 2021

Preprint

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Background: Lung adenocarcinoma (LUAD) is the commonest pathological subtype of lung-derived malignant tumor. Blocking the immune checkpoints interaction between programmed death-1 (PD-1) and programmed death ligand 1 (PD-L1) via naturalizing PD-1 or PD-L1 monoclonal antibody is proved to be a effective therapeutic method for drive gene negative LUAD. Dysregulation of circular RNA (circRNA) is a hallmark of cancer and has a critical role in the progression of cancers, including LUAD. However, the exact role of circular RUNX family transcription factor 1 (circRUNX1, hsa_circ_0002360) in LUAD remains unknown. Methods: The expression levels of circRUNX1, miR-4739, and proprotein convertase subtilisin/kexin type 9 (PCSK9) mRNA were examined by quantitative real-time polymerase chain reaction (qRT-PCR). PCSK9, histocompatibility complex I (MHC I), CD8, and Foxp3 protein expression was examined by immunohistochemistry (IHC) or western blot analysis. In vivo assay was carried out to determine the biological function of circRUNX1 on LUAD immune evasion in vivo. The binding relationship between miR-4739 and circRUNX1 or PCSK9 was predicted and verified by Starbase V3.0 online databases, dual-luciferase reporter assay, and RNA-pull down assay. Results: CircRUNX1 expression was frequently increased in LUAD tissues, and forced circRUNX1 expression was associated with poor prognosis, big tumor size, advanced stage, and resistance to anti-PD1 immunotherapy in LUAD patients. Functionally, circRUNX1 overexpression promoted LUAD immune evasion in vivo. In addition, our results demonstrated that circRUNX1 could sponge miR-4739, subsequently, upregulating the PCSK9 expression and promoting to LUAD immune evasion. Conclusion: circRUNX1 promoted cancer immune evasion and resistance to anti-PD1 immunotherapy by regulate miR-4739/PCSK9/MHC I axis in LUAD. Taken together, our findings indicate that circRUNX1 may be a promising therapeutic target for improve the anti-PD1 therapy effect in LUAD patients.

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Perspectives on Acquired Resistance to PD-1 Axis Inhibitors in Patients with Non–Small Cell Lung Cancer

Cited by 5 publications

References 21 publications

Circular RNA circFGFR1 promotes progression and anti-PD-1 resistance by sponging miR-381-3p in non-small cell lung cancer cells

Circular RNA circFGFR1 promotes progression and anti-PD-1 resistance by sponging miR-381-3p in non-small cell lung cancer cells

MicroRNAs in non‐small cell lung cancer: Gene regulation, impact on cancer cellular processes, and therapeutic potential

CircRUNX1 Drives Immune Evasion and anti-PD1 Immunotherapy Resistance in Lung Adenocarcinoma by the miR-4739/PCSK9/MHC I Axis

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