• Breast cancer
• Circular RNAs
• LncRNAs
• MicroRNAs
• Radioresistance
• Radiosensitivity

• Non-coding RNAs
• Radiation
• Radioresponse
• Radiotherapy
• Triple-negative breast cancer

• Female
• Humans
• Radiation Tolerance/genetics
• RNA, Untranslated/genetics
• Triple Negative Breast Neoplasms/genetics
• Triple Negative Breast Neoplasms/radiotherapy

• Chemotherapy resistance
• Metastasis
• TNBC
• Triple-negative
• miRNA-200
• miRNA-205

• Cancer
• Cancer stem cells
• MicroRNA
• Radiation
• Resistance

• Humans
• MicroRNAs/genetics
• MicroRNAs/metabolism
• Neoplasms/radiotherapy
• Neoplasms/genetics
• Neoplasms/pathology
• Radiation Tolerance/genetics
• Epithelial-Mesenchymal Transition
• DNA Repair

• ionizing radiation
• microRNAs
• radio-miRs
• radioresistance
• radiotherapy

• MicroRNAs/genetics
• MicroRNAs/metabolism
• Humans
• Radiation Tolerance/genetics
• Neoplasms/radiotherapy
• Neoplasms/genetics
• Neoplasms/metabolism
• DNA Repair
• Animals
• Gene Expression Regulation, Neoplastic/radiation effects
• DNA Damage

• Drug resistance
• Epithelial-mesenchymal transition
• Heterogeneity
• Prognosis
• RNA-based treatment methods
• Stemness
• Triple-Negative Breast Cancer
• Tumorigenesis
• miRNA

• Humans
• Female
• MicroRNAs/genetics
• MicroRNAs/therapeutic use
• Triple Negative Breast Neoplasms/pathology
• Carcinogenesis/genetics

• Cisplatin
• DNA damage
• HRD
• Synthetic lethal
• TNBC
• miR-26a-5p

• 81773197 National Natural Science Foundation of China
• 2017CFB412 Natural Science Foundation of Hubei Province

Radioresistance remains a major clinical challenge in cervical cancer therapy and results in tumor relapse and metastasis. Nevertheless, the detailed mechanisms are still largely enigmatic. This study was conducted to elucidate the prospective impacts of microRNA-29a (miR-29a) on the modulation of radioresistance-associated cervical cancer progression. Herein, we established two pairs of parental wild-type (WT) and radioresistant (RR) cervical cancer cells (CaSki and C33A), and we found that constant suppressed miR-29a, but not miR-29b/c, was exhibited in RR-clones that underwent a dose of 6-Gy radiation treatment. Remarkably, radioresistant clones displayed low radiosensitivity, and the reduced apoptosis rate resulted in augmented surviving fractions, measured by the clonogenic survival curve assay and the Annexin V/Propidium Iodide apoptosis assay, respectively. Overexpression of miR-29a effectively intensified the radiosensitivity and triggered the cell apoptosis in RR-clones. In contrast, suppressed miR-29a modestly abridged the radiosensitivity and abolished the cell apoptosis in WT-clones. Hence, ectopically introduced miR-29a into RR-clones notably attenuated the wound-healing rate and cell migration, whereas reduced miR-29a aggravated cell mobilities of WT-clones estimated via the in vitro wound-healing assay and time-lapse recording assay. Notably, we further established the in vivo short-term lung locomotion metastasis model in BALB/c nude mice, and we found that increased lung localization was shown after tail-vein injection of RR-CaSki cells compared to those of WT-CaSki cells. Amplified miR-29a significantly eliminated the radioresistance-enhanced lung locomotion. Our data provide evidence suggesting that miR-29a is a promising microRNA signature in radioresistance of cervical cancer cells and displays multifaceted innovative roles involved in anti-radioresistance, escalated apoptosis, and anti-cell migration/metastasis. Amalgamation of a nucleoid-based strategy (miR-29a) together with conventional radiotherapy may be an innovative and eminent strategy to intensify the radiosensitivity and further protect against the subsequent radioresistance and the potential metastasis in cervical cancer treatment.

• Radiation therapy
• Radioresistance
• Radiosensitization
• Triple-negative breast cancer
• microRNA

• Breast cancer
• Non-coding RNA
• Radiation resistance
• Signal transduction

• breast cancer
• long non-coding RNAs
• microRNAs
• non-coding RNAs
• radioresistance
• triple negative breast-cancer

• MiRNA mimics
• antagomirs
• anticancer therapeutics
• drug target
• microRNA
• oncomirs
• tumor suppressor miRNAs

• AKT signaling pathway
• Breast cancer
• PTEN
• RNAs
• dysregulation.
• microRNA

• Endometritis
• Inflammation
• LGR4
• miR-193a-3p

• Breast cancer
• Chemotherapy
• Hormone and targeted therapy
• Radiotherapy
• microRNA

• Antineoplastic Combined Chemotherapy Protocols/pharmacology
• Antineoplastic Combined Chemotherapy Protocols/therapeutic use
• Biomarkers, Tumor/antagonists & inhibitors
• Biomarkers, Tumor/metabolism
• Breast Neoplasms/genetics
• Breast Neoplasms/therapy
• Drug Resistance, Neoplasm/drug effects
• Drug Resistance, Neoplasm/genetics
• Female
• Gene Expression Regulation, Neoplastic/drug effects
• Humans
• MicroRNAs/antagonists & inhibitors
• MicroRNAs/metabolism
• Molecular Targeted Therapy/methods
• Radiation Tolerance/drug effects
• Radiation Tolerance/genetics

• Apoptosis/drug effects
• BRCA1 Protein/deficiency
• BRCA1 Protein/metabolism
• Cell Death/drug effects
• Cell Line, Tumor
• Cell Survival/drug effects
• DNA Damage
• DNA Repair/drug effects
• Doxorubicin/pharmacology
• Fluorescence
• High-Throughput Screening Assays
• Homologous Recombination/drug effects
• Humans
• Mitoxantrone/pharmacology
• Neoplasms/metabolism
• Neoplasms/pathology
• Protein Binding/drug effects
• Quinacrine/pharmacology
• Rad52 DNA Repair and Recombination Protein/metabolism
• Replication Protein A/metabolism
• Small Molecule Libraries/pharmacology

• P30 CA036727 NCI NIH HHS

• Breast cancer
• miRNAs
• radioresistance
• radiosensitivity
• radiotherapy

• DNA damage
• RAD21
• hepatocellular carcinoma
• ionizing radiation-based therapy
• miR-320b

• Breast cancer
• Diagnosis
• Prognosis
• Signaling pathways
• Therapeutic resistnce
• miRNA cluster

• Breast Neoplasms/genetics
• Disease Progression
• Female
• Gene Expression Regulation, Neoplastic
• Genetic Variation
• Humans
• MicroRNAs/genetics
• Multigene Family
• Prognosis
• Signal Transduction

• Wellcome-Trust DBT Intermediate

• miRNAs
• pathogenesis
• prognosis
• radiotherapy
• rectal cancer

Introduction: Chemotherapy is still the standard of care for triple-negative breast cancers (TNBCs). Here, we investigated miR-302b as a therapeutic tool to enhance cisplatin sensitivity in vivo and unraveled the molecular mechanism. Materials and Methods: TNBC-xenografted mice were treated with miR-302b or control, alone or with cisplatin. Genome-wide transcriptome analysis and independent-validation of Integrin Subunit Alpha 6 (ITGA6) expression was assessed on mice tumor samples. Silencing of ITGA6 was performed to evaluate cisplatin response in vitro. Further, potential transcription factors of ITGA6 (E2F transcription facor 1 (E2F1), E2F transcription factor 2 (E2F2), and Yin Yang 1 (YY1)) were explored to define the miRNA molecular mechanism. The miR-302b expression was also assessed in TNBC patients treated with chemotherapy. Results: The miR–302b-cisplatin combination significantly impaired tumor growth versus the control through indirect ITGA6 downregulation. Indeed, ITGA6 was downmodulated in mice treated with miR-302b–cisplatin, and ITGA6 silencing increased drug sensitivity in TNBC cells. In silico analyses and preclinical assays pointed out the regulatory role of the E2F family and YY1 on ITGA6 expression under miR-302b–cisplatin treatment. Finally, miR-302b enrichment correlated with better overall survival in 118 TNBC patients. Conclusion: MiR-302b can be exploited as a new therapeutic tool to improve the response to chemotherapy, modulating the E2F family, YY1, and ITGA6 expression. Moreover, miR-302b could be defined as a new prognostic factor in TNBC patients.

• cisplatin
• drug response
• microRNAs
• triple-negative breast cancer

Ionizing radiation may be of both artificial and natural origin and causes cellular damage in living organisms. Radioactive isotopes have been used significantly in cancer therapy for many years. The formation of DNA double-strand breaks (DSBs) is the most dangerous effect of ionizing radiation on the cellular level. After irradiation, cells activate a DNA damage response, the molecular path that determines the fate of the cell. As an important element of this, homologous recombination repair is a crucial pathway for the error-free repair of DNA lesions. All components of DNA damage response are regulated by specific microRNAs. MicroRNAs are single-stranded short noncoding RNAs of 20–25 nt in length. They are directly involved in the regulation of gene expression by repressing translation or by cleaving target mRNA. In the present review, we analyze the biological mechanisms by which miRNAs regulate cell response to ionizing radiation-induced double-stranded breaks with an emphasis on DNA repair by homologous recombination, and its main component, the RAD51 recombinase. On the other hand, we discuss the ability of DNA damage response proteins to launch particular miRNA expression and modulate the course of this process. A full understanding of cell response processes to radiation-induced DNA damage will allow us to develop new and more effective methods of ionizing radiation therapy for cancers, and may help to develop methods for preventing the harmful effects of ionizing radiation on healthy organisms.

• DNA damage response
• cancer therapy
• double-strand DNA breaks
• ionizing radiation
• microRNA

• circRNA
• lncRNA
• miRNA
• non-coding RNA
• radiation response
• radiotherapy

• 2017/27/B/NZ1/00877 National Science Centre Poland
• 2015/19/D/NZ1/03443 National Science Centre Poland
• 2015/19/B/ST7/02984 National Science Centre Poland

As a novel class of noncoding RNAs, microRNAs (miRNAs) can effectively silence their target genes at the posttranscriptional level. Various biological processes, such as cell proliferation, differentiation, and motility, are regulated by miRNAs. In different diseases and different stages of disease, miRNAs have various expression patterns, which makes them candidate prognostic markers and therapeutic targets. Abnormal miRNA expression has been detected in numerous neoplastic diseases in humans, which indicates the potential role of miRNAs in tumorigenesis. Previous studies have indicated that miRNAs are involved in nearly the entire process of tumor development. MicroRNA‐302a, miR‐302b, miR‐302c, miR‐302d, and miR‐367 are members of the miR‐302/367 cluster that plays various biological roles in diverse neoplastic diseases by targeting different genes. These miRNAs have been implicated in several unique characteristics of cancer, including the evasion of growth suppressors, the sustained activation of proliferative signaling, the evasion of cell death and senescence, and the regulation of angiogenesis, invasion, and metastasis. This review provides a critical overview of miR‐302/367 cluster dysregulation and the subsequent effects in cancer and highlights the vast potential of members of this cluster as therapeutic targets and novel biomarkers.

• MIRN302
• biological phenomena
• cell dedifferentiation
• neoplasm
• therapy

• Apoptosis
• LncRNA SBF2-AS1
• MicroRNA-302a
• Muscleblind-like 3
• Non-small cell lung cancer
• Proliferation
• Radiosensitivity

• Diagnosis
• microRNA
• prognosis
• treatment
• triple-negative breast cancer

Triple-negative breast cancer (TNBC) is the most aggressive, prevalent, and distinct subtype of breast cancer characterized by high recurrence rates and poor clinical prognosis, devoid of both predictive markers and potential therapeutic targets. MicroRNAs (miRNA/miR) are a family of small, endogenous, non-coding, single-stranded regulatory RNAs that bind to the 3′-untranslated region (3′-UTR) complementary sequences and downregulate the translation of target mRNAs as post-transcriptional regulators. Dysregulation miRNAs are involved in broad spectrum cellular processes of TNBC, exerting their function as oncogenes or tumor suppressors depending on their cellular target involved in tumor initiation, promotion, malignant conversion, and metastasis. In this review, we emphasize on masses of miRNAs that act as oncogenes or tumor suppressors involved in epithelial–mesenchymal transition (EMT), maintenance of stemness, tumor invasion and metastasis, cell proliferation, and apoptosis. We also discuss miRNAs as the targets or as the regulators of dysregulation epigenetic modulation in the carcinogenesis process of TNBC. Furthermore, we show that miRNAs used as potential classification, prognostic, chemotherapy and radiotherapy resistance markers in TNBC. Finally, we present the perspective on miRNA therapeutics with mimics or antagonists, and focus on the challenges of miRNA therapy. This study offers an insight into the role of miRNA in pathology progression of TNBC.

• chemotherapy and radiotherapy resistance
• epigenetic mechanisms
• miRNAs
• prognosis
• therapeutic strategies
• triple-negative breast cancer (TNBC)
• tumorigenesis

• Biomarkers, Tumor/genetics
• Carcinogenesis/genetics
• Drug Resistance, Neoplasm/genetics
• Humans
• MicroRNAs/genetics
• Triple Negative Breast Neoplasms/diagnosis
• Triple Negative Breast Neoplasms/genetics
• Triple Negative Breast Neoplasms/pathology
• Triple Negative Breast Neoplasms/therapy

• animal models
• antagomiR
• cellular models
• human models
• lung diseases
• miRNAs

• Animals
• Antagomirs/administration & dosage
• Antagomirs/genetics
• Biomarkers
• Cell Line
• Cells, Cultured
• Gene Expression Regulation
• Humans
• Lung Diseases/diagnosis
• Lung Diseases/genetics
• Lung Diseases/metabolism
• Lung Diseases/therapy
• MicroRNAs/genetics
• Models, Animal
• RNA Interference

• CTNNB1
• ROCK1
• RhoA
• c-MYC
• miR-381
• triple-negative breast cancer

• Cancer biomarkers
• TNBC
• miRNA
• miRNA-based therapy

• Biochemistry
• Biomedical engineering
• Biotechnology
• Cancer research
• Cell biology
• Developmental biology
• Genetics
• Molecular biology

• Invasion
• Metastasis
• Triple-negative breast cancer
• ZEB2
• epithelial–mesenchymal transition
• miR-124

• Cancer
• Cell cycle
• Homologous recombination
• Replication stress
• Tumor suppressor

MicroRNAs are a class of small non-coding regulatory RNAs playing key roles in cancer. Breast cancer is the most common female malignancy worldwide and is categorized into four molecular subtypes: luminal A and B, HER2+ and triple-negative breast cancer (TNBC). Despite the development of multiple targeted therapies for luminal and HER2+ breast tumors, TNBC lacks specific therapeutic approaches, thus they are treated mainly with radio- and chemotherapy. The effectiveness of these therapeutic regimens is based on their ability to induce DNA damage, which is differentially resolved and repaired by normal vs. cancer cells. Recently, drugs directly targeting DNA repair mechanisms, such as PARP inhibitors, have emerged as attractive candidates for the future molecular targeted-therapy in breast cancer. These compounds prevent cancer cells to appropriate repair DNA double strand breaks and induce a phenomenon called synthetic lethality, that results from the concurrent inhibition of PARP and the absence of functional BRCA genes which prompt cell death. MicroRNAs are relevant players in most of the biological processes including DNA damage repair mechanisms. Consistently, the downregulation of DNA repair genes by miRNAs have been probe to improve the therapeutic effect of genotoxic drugs. In this review, we discuss how microRNAs can sensitize cancer cells to DNA-damaging drugs, through the regulation of DNA repair genes, and examine the most recent findings on their possible use as a therapeutic tools of treatment response in breast cancer.

• DNA damage response
• DNA repair
• DNA-damaging drugs
• breast cancer
• microRNAs

• Gastrointestinal cancer cells
• Ionizing radiation
• MicroRNA
• RAD23B
• Radiosensitivity

Genetic alterations driving aberrant activation of the survival kinase Protein Kinase B (Akt) are observed with high frequency during malignant transformation and cancer progression. Oncogenic gene mutations coding for the upstream regulators or Akt, e.g., growth factor receptors, RAS and phosphatidylinositol-3-kinase (PI3K), or for one of the three Akt isoforms as well as loss of the tumor suppressor Phosphatase and Tensin Homolog on Chromosome Ten (PTEN) lead to constitutive activation of Akt. By activating Akt, these genetic alterations not only promote growth, proliferation and malignant behavior of cancer cells by phosphorylation of various downstream signaling molecules and signaling nodes but can also contribute to chemo- and radioresistance in many types of tumors. Here we review current knowledge on the mechanisms dictating Akt’s activation and target selection including the involvement of miRNAs and with focus on compartmentalization of the signaling network. Moreover, we discuss recent advances in the cross-talk with DNA damage response highlighting nuclear Akt target proteins with potential involvement in the regulation of DNA double strand break repair.

• Akt
• Akt targets
• PI3K
• Protein Kinase B
• cellular radiation response
• signaling network

It has historically been accepted that incorrectly repaired DNA double strand breaks (DSBs) are the principal lesions of importance regarding mutagenesis, and long-term biological effects associated with ionizing radiation. However, radiation may also cause dysregulation of epigenetic processes that can lead to altered gene function and malignant transformation, and epigenetic alterations are important causes of miRNAs dysregulation in cancer.

Patched1 heterozygous (Ptch1^+/−) mice, characterized by aberrant activation of the Sonic hedgehog (Shh) signaling pathway, are a well-known murine model of spontaneous and radiation-induced medulloblastoma (MB), a common pediatric brain tumor originating from neural granule cell progenitors (GCPs). The high sensitivity of neonatal Ptch1^+/− mice to radiogenic MB is dependent on deregulation of the Ptch1 gene function. Ptch1 activates a growth and differentiation programme that is a strong candidate for regulation through the non-coding genome. Therefore we carried out miRNA next generation sequencing in ex vivo irradiated and control GCPs, isolated and purified from cerebella of neonatal WT and Ptch1^+/− mice. We identified a subset of miRNAs, namely let-7 family and miR-17∼92 cluster members, whose expression is altered in GCPs by radiation alone, or by synergistic interaction of radiation with Shh-deregulation. The same miRNAs were further validated in spontaneous and radiation-induced MBs from Ptch1^+/− mice, confirming persistent deregulation of these miRNAs in the pathogenesis of MB.

Our results support the hypothesis that miRNAs dysregulation is associated with radiosensitivity of GCPs and their neoplastic transformation in vivo.

• GCPs
• Shh
• X-rays
• medulloblastoma
• miRNA

Osteosarcoma is one of the most frequent types of primary malignant bone neoplasm in children and adolescents. Despite advancements developed in therapeutic modalities, the 5-year overall survival rates for patients with metastatic osteosarcoma disease remain poor. The present study aimed to investigate the expression level of microRNA-302a (miR-302a) in osteosarcoma tissues and cell lines, and the biological roles of miR-302a in osteosarcoma cells. In addition, the molecular mechanism underlying its tumor suppressive roles was evaluated. miR-302a expression in osteosarcoma tissues and cell lines was detected using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Following transfection of miR-302a mimics or IGF-1R siRNA, transwell migration and invasion, luciferase reporter assay RT-qPCR and western blot assays were conducted in osteosarcoma cells. In the present study, the data demonstrated that miR-302a was frequently reduced in osteosarcoma tissue and cell lines. In addition, the expression of miR-302a was correlated with metastatic features of patients with osteosarcoma. Restoration of miR-302a expression significantly inhibited the migration and invasion capacity of osteosarcoma cells. Mechanistic studies indicated that insulin-like growth factor 1 receptor (IGF-1R) was a direct target gene of miR-302a. Overexpression of miR-302a resulted in decreased expression of IGF-1R at the mRNA and protein levels. Furthermore, the knockdown IGF-1R mimicked the functions of miR-302a overexpression on osteosarcoma cell migration and invasion. Collectively, the results of the current study indicate that miR-302a acts as a metastasis suppressing miRNA and could be investigated as a therapeutic target for the treatment of patients with osteosarcoma to prevent metastasis.

• insulin-like growth factor 1 receptor
• invasion
• metastasis
• microRNA-302a
• migration
• osteosarcoma

• DNA demethylation
• Epigenetic reprogramming
• Induced pluripotent stem cell
• MicroRNA
• Pluripotency
• miR-302

• Biogenesis
• Cancer
• Circulating miRNA
• Drug development
• Heart disease
• Intronic miRNA
• Mechanism
• Noncoding RNAs
• Small RNA
• Transposons
• iPSCs
• miRNA
• siRNA

• Animals
• Biomarkers
• Circulating MicroRNA
• Gene Expression Regulation
• Gene Silencing
• Heart Diseases/blood
• Heart Diseases/diagnosis
• Heart Diseases/genetics
• Humans
• Induced Pluripotent Stem Cells/cytology
• Induced Pluripotent Stem Cells/metabolism
• MicroRNAs/genetics
• Neoplasms/blood
• Neoplasms/diagnosis
• Neoplasms/genetics
• RNA Interference
• RNA, Messenger/genetics
• RNA, Small Untranslated/genetics

• Breast cancer
• CRKL
• HDAC inhibitor
• MiR-200c
• SAHA

• Adaptor Proteins, Signal Transducing/genetics
• Adaptor Proteins, Signal Transducing/metabolism
• Breast Neoplasms/genetics
• Breast Neoplasms/metabolism
• Cell Proliferation/drug effects
• Cell Proliferation/physiology
• Female
• Gene Targeting
• Histone Deacetylase Inhibitors/pharmacology
• Humans
• MCF-7 Cells
• MicroRNAs/biosynthesis
• MicroRNAs/genetics
• Neoplasm Invasiveness/genetics
• Nuclear Proteins/genetics
• Nuclear Proteins/metabolism

• R01 CA109366 NCI NIH HHS
• R01 CA165306 NCI NIH HHS
• T32 GM008602 NIGMS NIH HHS

Radiotherapy is one of the most important treatment options for localized early-stage or advanced-stage prostate cancer (CaP). Radioresistance (relapse after radiotherapy) is a major challenge for the current radiotherapy. There is great interest in investigating mechanisms of radioresistance and developing novel treatment strategies to overcome radioresistance. MicroRNAs (miRNAs) are small, non-coding RNAs that regulate gene expression at the post-transcriptional level, participating in numerous physiological and pathological processes including cancer invasion, progression, metastasis and therapeutic resistance. Emerging evidence indicates that miRNAs play a critical role in the modulation of key cellular pathways that mediate response to radiation, influencing the radiosensitivity of the cancer cells through interplaying with other biological processes such as cell cycle checkpoints, apoptosis, autophagy, epithelial-mesenchymal transition and cancer stem cells. Here, we summarize several important miRNAs in CaP radiation response and then discuss the regulation of the major signalling pathways and biological processes by miRNAs in CaP radiotherapy. Finally, we emphasize on microRNAs as potential predictive biomarkers and/or therapeutic targets to improve CaP radiosensitivity.

• MicroRNAs
• Prostate cancer
• Radioresistance
• Radiotherapy
• Signalling pathway.

• DNA damage response
• Rad52
• pre‐clinical model
• squamous cell carcinoma of the lung
• tumor growth

• Cell Survival/genetics
• Cell Survival/physiology
• DNA Damage
• DNA Repair
• Gene Expression Regulation, Neoplastic/physiology
• Humans
• Neoplasms/metabolism
• Rad52 DNA Repair and Recombination Protein/genetics
• Rad52 DNA Repair and Recombination Protein/metabolism

• R01 CA134682 NCI NIH HHS
• U19 CA148127 NCI NIH HHS
• R01 CA208648 NCI NIH HHS
• R01 CA205633 NCI NIH HHS
• R01 CA223804 NCI NIH HHS

We investigated whether radiation influences the susceptibility of non-small cell lung cancer (NSCLC) cells to NK cell mediated cytotoxicity. We found radiation treatment increased expression of programmed cell death ligand 1 (PD-L1), but decreased NK group 2, member D (NKG2D) ligand expressions in A549 and H157 NSCLC cells. Both types of changes would have protected tumor cells from the cytotoxic action of NK cells. Consistently, we detected similar alteration in these molecules in radioresistant A549R26-1 and H157R24-1 subline cells. Higher PD-L1 level was also observed in tumors of A549R26-1 cell-derived xenografts than tumors of parental A549 (A549P) cell-derived xenografts. Accordingly, we found radioresistant cells were more resistant to the cytotoxic action of NK cells than parental cells, and such resistance was decreased when neutralizing antibody (Ab) of PD-L1 was added to the radioresistant cell/NK cell co-cultures. In mechanism studies, we found that IL-6-MEK/Erk signaling contributed most significantly to the up-regulation of PD-L1/down-regulation of NKG2D ligands in radioresistant cells. The addition of the MEK/Erk inhibitor increased the susceptibility of A549R26-1 and H157R24-1 cells to NK-cell cytotoxicity while no significant effect was observed in parental cells. Moreover, we detected enhanced NK-cell cytotoxicity to radioresistant cells when PD-L1 Ab and MEK/Erk inhibitor were added together to co-cultures of tumor/NK cells compared to when PD-L1 Ab was used alone. We suggest that combined use of PD-L1 Ab and MEK/Erk inhibitor may offer better therapeutic benefits than PD-L1 Ab alone to treat NSCLC patients who are receiving radiotherapy or who are at the radioresistant stage.

• MEK/Erk
• NK cytotoxicity
• NKG2D
• PD-L1
• radioresistant lung cancer