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Radioresistance of Non-Small Cell Lung Cancers and Therapeutic Perspectives.

ABSTRACT: Survival in unresectable locally advanced stage non-small cell lung cancer (NSCLC) patients remains poor despite chemoradiotherapy. Recently, adjuvant immunotherapy improved survival for these patients but we are still far from curing most of the patients with only a 57% survival remaining at 3 years. This poor survival is due to the resistance to chemoradiotherapy, local relapses, and distant relapses. Several biological mechanisms have been found to be involved in the chemoradioresistance such as cancer stem cells, cancer mutation status, or the immune system. New drugs to overcome this radioresistance in NSCLCs have been investigated such as radiosensitizer treatments or immunotherapies. Different modalities of radiotherapy have also been investigated to improve efficacity such as dose escalation or proton irradiations. In this review, we focused on biological mechanisms such as the cancer stem cells, the cancer mutations, the antitumor immune response in the first part, then we explored some strategies to overcome this radioresistance in stage III NSCLCs with new drugs or radiotherapy modalities.

SUBMITTER: Cesaire M

PROVIDER: S-EPMC9221493 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature

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Radioresistance of Non-Small Cell Lung Cancers and Therapeutic Perspectives.

Césaire Mathieu M Montanari Juliette J Curcio Hubert H Lerouge Delphine D Gervais Radj R Demontrond Pierre P Balosso Jacques J Chevalier François F

Cancers 20220608 12

Survival in unresectable locally advanced stage non-small cell lung cancer (NSCLC) patients remains poor despite chemoradiotherapy. Recently, adjuvant immunotherapy improved survival for these patients but we are still far from curing most of the patients with only a 57% survival remaining at 3 years. This poor survival is due to the resistance to chemoradiotherapy, local relapses, and distant relapses. Several biological mechanisms have been found to be involved in the chemoradioresistance such ...[more]

PMID: 35740495

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Project description:BackgroundNon-small cell lung cancer (NSCLC), a leading cause of cancer deaths, represents a heterogeneous group of neoplasms, mostly comprising squamous cell carcinoma (SCC), adenocarcinoma (AC) and large-cell carcinoma (LCC). The objectives of this study were to utilize integrated genomic data including copy-number alteration, mRNA, microRNA expression and candidate-gene full sequencing data to characterize the molecular distinctions between AC and SCC.MethodsComparative genomic hybridization followed by mutational analysis, gene expression and miRNA microarray profiling were performed on 123 paired tumor and non-tumor tissue samples from patients with NSCLC.ResultsAt DNA, mRNA and miRNA levels we could identify molecular markers that discriminated significantly between the various histopathological entities of NSCLC. We identified 34 genomic clusters using aCGH data; several genes exhibited a different profile of aberrations between AC and SCC, including PIK3CA, SOX2, THPO, TP63, PDGFB genes. Gene expression profiling analysis identified SPP1, CTHRC1 and GREM1 as potential biomarkers for early diagnosis of the cancer, and SPINK1 and BMP7 to distinguish between AC and SCC in small biopsies or in blood samples. Using integrated genomics approach we found in recurrently altered regions a list of three potential driver genes, MRPS22, NDRG1 and RNF7, which were consistently over-expressed in amplified regions, had wide-spread correlation with an average of ~800 genes throughout the genome and highly associated with histological types. Using a network enrichment analysis, the targets of these potential drivers were seen to be involved in DNA replication, cell cycle, mismatch repair, p53 signalling pathway and other lung cancer related signalling pathways, and many immunological pathways. Furthermore, we also identified one potential driver miRNA hsa-miR-944.ConclusionsIntegrated molecular characterization of AC and SCC helped identify clinically relevant markers and potential drivers, which are recurrent and stable changes at DNA level that have functional implications at RNA level and have strong association with histological subtypes.

Project description:Background: Radiation therapy plays an important role in the treatment of patients with non-small cell lung cancer (NSCLC). However, the radiocurability is greatly limited because of radioresistance which leads to treatment failure, tumor recurrence, and metastasis. Cancer stem cell (CSC) has been identified as the main factor that contributes to radiation resistance. SOX2, one of the transcription factors specifically expressed in CSC, is involved in tumorigenesis, progression, and maintenance of cell stemness. But the association between SOX2 and NSCLC radioresistance is not clear now. Methods: We constructed the radiotherapy-resistant cell line of NSCLC by multiple radiotherapy treatments. Colony formation assay, western blot, and immunofluorescence were performed to detect the radiosensitivity of cells. Western blot, qRT-PCR, and sphere formation assay were used to detect CSC characteristics of cells. Wound healing assay and Transwell assay were used to determine cell migration motility. The SOX2-upregulated model and SOX2-downregulated model was constructed by lentivirus transduction. Finally, the expression and clinical relevance of SOX2 in NSCLC were investigated by bioinformatics analysis based on TCGA and GEO datasets. Results: The expression of SOX2 was increased in radioresistant cells and a trend of dedifferentiation were observed. The results of wound healing assay and Transwell assay showed that SOX2 overexpression significantly promote the migration and invasion of NSCLC cells. Mechanistically, overexpression of SOX2 enhanced radioresistance and DNA damage repair capability of parental cells, while down-regulation of SOX2 led to decreased radioresistance and DNA repair ability in radioresistant cells, all of which were related to cells dedifferentiation regulated by SOX2. In addition, bioinformatics analysis show that high expression of SOX2 was strongly associated with the progression and poor prognosis of patients with NSCLC. Conclusions: Our study revealed that SOX2 regulates radiotherapy resistance in NSCLC via promoting cell dedifferentiation. Therefore, SOX2 may be a promising therapeutic target for overcoming radioresistance in NSCLC, providing a new perspective to improve the curative effect.

Dataset Information

Radioresistance of Non-Small Cell Lung Cancers and Therapeutic Perspectives.

Publications

Radioresistance of Non-Small Cell Lung Cancers and Therapeutic Perspectives.

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