Resistance to radioimmunotherapy is one of the primary causes of treatment failure in lung cancer patients; however, the underlying mechanisms remain inadequately understood. In this study, we found that the E2/E3 hybrid ubiquitin enzyme UBE2O interacted with CDKL1, facilitating its ubiquitination and subsequent degradation at the K21 residue and thereby negatively regulating the stability of the CDKL1 protein in lung cancer. Silencing UBE2O stabilized CDKL1 to inhibit YBX1-mediated PD-L1 transcription, which consequently promoted the infiltration and activation of CD8+ T cells, thereby enhancing the antitumor immune response in lung cancer. Furthermore, targeting UBE2O in combination with radiotherapy and anti-PD-L1 immunotherapy resulted in stronger antitumor efficacy in lung cancer models. Notably, the UBE2O crosslinking inhibitor arsenic trioxide (ATO) reduced PD-L1 expression and enhanced the efficacy of radioimmunotherapy in preclinical lung cancer models while exhibiting acceptable short-term tolerability. Our findings indicate that targeting the UBE2O/CDKL1 axis may represent a highly promising strategy for increasing lung cancer sensitization to radioimmunotherapy.

To evaluate the efficacy and safety of third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in combination with radiotherapy (RT) for patients with advanced non-small cell lung cancer (NSCLC) harboring typical EGFR mutations. Patients who received treatment with third-generation EGFR-TKIs alone or in combination with RT were retrospectively enrolled at a single center. The primary endpoint was progression-free survival (PFS). Differences in PFS between the two groups were assessed via the Kaplan–Meier method. Additionally, a subgroup analysis was conducted to further explore the effect of thoracic RT combined with EGFR-TKIs. This study included a total of 260 patients, among whom 81 patients received third-generation EGFR-TKIs and 179 patients received third-generation EGFR-TKIs plus RT. There was a significant difference in median PFS (mPFS) (13.0 versus 18.1 months, P = 0.0003) between the two groups. Moreover, third-generation EGFR-TKIs plus thoracic RT significantly improved the mPFS (13.0 versus 23.7 months, P < 0.0001). We observed that third-generation EGFR-TKIs plus RT increased the incidence of pneumonia, but all the cases were grade 1 or 2. The addition of RT can delay the occurrence of acquired resistance to third-generation EGFR-TKIs, thereby significantly prolonging PFS in advanced NSCLC patients. RT for primary lung lesions exhibited a significant synergistic effect with EGFR-TKI treatment, and the adverse events of the combination therapy were acceptable.

Epithelioid inflammatory myofibroblastic sarcoma (EIMS) is a rare and highly aggressive mesenchymal neoplasm that is frequently associated with anaplastic lymphoma kinase (ALK) gene fusion. Surgical resection remains the cornerstone of treatment for patients with early- and intermediate-stage EIMS; however, a standardized therapeutic approach for advanced-stage EIMS has yet to be established. Primary pulmonary EIMS is exceedingly rare, with only a limited number of cases reported in the literature. While treatment with ALK-tyrosine kinase inhibitors (TKIs) is considered a viable therapeutic option, and clinical outcomes with monotherapy using ALK-TKIs have frequently been suboptimal. This study presents a case of advanced primary pulmonary EIMS with a TPM3-ALK fusion. The patient received first-line targeted therapy with the second-generation ALK-TKI Ensartinib, in conjunction with radiotherapy for residual and metastatic lesions. This treatment regimen resulted in significant tumor reduction and sustained disease control. The progression-free survival (PFS) exceeded 32 months, with no significant treatment-related adverse events observed. This study investigates the feasibility of combining targeted therapy with local radiotherapy, guided by genetic testing, to offer novel treatment strategies for patients with advanced primary pulmonary EIMS.

Radioresistance is one of the main reasons for the recurrence and metastasis of non-small cell lung cancer. Cyclin Y has been implicated in various cellular processes such as cell growth, proliferation, autophagy, and tumor progression. However, the function and regulatory mechanism of Cyclin Y in lung cancer radioresistance remain poorly understood. In this study, we find that Cyclin Y is overexpressed in non-small cell lung cancer and correlates with poor prognosis. Furthermore, knockdown of Cyclin Y results in inhibited cell growth and proliferation, increases DNA damage, impairs DNA damage repair, and enhances radiosensitivity in vitro and in vivo. Mechanistically, we uncover that Cyclin Y interacts with Chk1 and positively regulate both the mRNA and protein levels of RRM2, resulting in increased STAT3 phosphorylation. Rescue experiments confirm that the effects of Cyclin Y on lung cancer are mediated partially by RRM2. Collectively, we reveal for the first time that Cyclin Y promotes lung cancer radioresistance by binding to Chk1 to activate RRM2/STAT3 signaling, indicating that targeting Cyclin Y may be a promising strategy for enhancing the efficacy of radiotherapy in the treatment of non-small cell lung cancer.

PURPOSE:Radioresistance of lung cancer poses a significant challenge when it comes to the treatment of advanced, recurrent, and metastatic cases. Ovarian tumor domain ubiquitin aldehyde binding 1 (OTUB1) is a key member of the deubiquitinase OTU superfamily. This protein is involved in various cellular functions, including cell proliferation, iron death, lipid metabolism, and cytokine secretion as well as immune response processes. However, its specific role and molecular mechanism in lung cancer radioresistance remain to be clarified. METHODS AND MATERIALS:The expression levels of OTUB1 in paired lung cancer tissues were determined by immunohistochemistry. In vitro and in vivo experiments were conducted to investigate the impact of OTUB1 on the growth and proliferation of lung cancer. Coimmunoprecipitation and Western blotting techniques were performed to examine the interaction between OTUB1 and CHK1. The DNA damage response was measured by comet tailing and immunofluorescence staining. KEGG pathways and Gene Ontology terms were analyzed based on RNA sequencing. RESULTS:Our findings reveal a high frequency of OTUB1 overexpression, which is associated with an unfavorable prognosis in patients with lung cancer. Through comprehensive investigations, we demonstrate that OTUB1 depletion impairs the process of DNA damage repair and overcomes radioresistance. In terms of the underlying mechanism, our study uncovers that OTUB1 deubiquitinates and stabilizes CHK1, which enhances CHK1 stability, thereby regulating DNA damage and repair. Additionally, we identify CHK1 as the primary downstream effector responsible for mediating the functional effects exerted by OTUB1 specifically in lung cancer. Importantly, OTUB1 has the potential to be a valuable marker for improving the efficacy of radiation therapy for lung adenocarcinoma. CONCLUSIONS:These findings unveil a novel role for OTUB1 in enhancing radioresistance by deubiquitination and stabilization of the expression of CHK1 in lung cancer and indicate that targeting OTUB1 holds great potential as an effective therapeutic approach for enhancing the efficacy of radiation therapy in lung cancer.

Background The evasion of the immune response by tumor cells through programmed death-ligand 1 (PD-L1) has been identified as a factor contributing to resistance to radioimmunotherapy in lung cancer patients. However, the precise molecular mechanisms underlying the regulation of PD-L1 remain incompletely understood. This study aimed to investigate the role of cyclin-dependent kinase-like 1 (CDKL1) in the modulation of PD-L1 expression and the response to radioimmunotherapy in lung cancer. Methods The tumorigenic roles of CDKL1 were assessed via cell growth, colony formation, and EdU assays and an in vivo nude mouse xenograft model. The in vitro radiosensitization effect of CDKL1 was evaluated using a neutral comet assay, γH2AX foci formation analysis, and a clonogenic cell survival assay. The protein‒protein interactions were confirmed via coimmunoprecipitation and GST pulldown assays. The regulation of PD-L1 by CDKL1 was evaluated via chromatin immunoprecipitation (ChIP), real-time quantitative PCR, and flow cytometry analysis. An in vitro conditioned culture model and an in vivo C57BL/6J mouse xenograft model were developed to detect the activation markers of CD8 + T cells and evaluate the efficacy of CDKL1 overexpression combined with radiotherapy (RT) and an anti-PD-L1 antibody in treating lung cancer. Results CDKL1 was downregulated and suppressed the growth and proliferation of lung cancer cells and increased radiosensitivity in vitro and in vivo. Mechanistically, CDKL1 interacted with the transcription factor YBX1 and decreased the binding affinity of YBX1 for the PD-L1 gene promoter, which consequently inhibits the expression of PD-L1, ultimately leading to the activation of CD8 + T cells and the inhibition of immune evasion in lung cancer. Moreover, the combination of CDKL1 overexpression, RT, and anti-PD-L1 antibody therapy exhibited the most potent antitumor efficacy against lung cancer. Conclusions Our findings demonstrate that CDKL1 plays a crucial role in regulating PD-L1 expression, thereby enhancing the antitumor effects of radioimmunotherapy. These results suggest that CDKL1 may be a promising therapeutic target for the treatment of lung cancer.

Radioresistance is a major constraint on the efficacy of lung cancer radiotherapy, but its mechanism has not been fully elucidated. Here, we found that FBXO22 was aberrantly highly expressed in lung cancer and that FBXO22 knockdown increased the radiosensitivity of lung cancer cells. Mechanistically, FBXO22 promoted Rad51 gene transcription by increasing the level of FOXM1 at the Rad51 promoter, thereby inducing the formation of lung cancer radioresistance. Furthermore, we found that deguelin, a potential inhibitor of FBXO22, enhanced radiosensitivity in an FBXO22/Rad51-dependent manner and was safely tolerated in vivo. Collectively, our results illustrate that FBXO22 induces lung cancer radioresistance by activating the FOXM1/Rad51 axis and provide preclinical evidence for the clinical translation of this critical target.

Radioresistance is a key clinical constraint on the efficacy of radiotherapy in lung cancer patients. REV1 DNA directed polymerase (REV1) plays an important role in repairing DNA damage and maintaining genomic stability. However, its role in the resistance to radiotherapy in lung cancer is not clear. This study aims to clarify the role of REV1 in lung cancer radioresistance, identify the intrinsic mechanisms involved, and provide a theoretical basis for the clinical translation of this new target for lung cancer treatment. The effect of targeting REV1 on the radiosensitivity was verified by in vivo and in vitro experiments. RNA sequencing (RNA-seq) combined with nontargeted metabolomics analysis was used to explore the downstream targets of REV1. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to quantify the content of specific amino acids. The coimmunoprecipitation (co-IP) and GST pull-down assays were used to validate the interaction between proteins. A ubiquitination library screening system was constructed to investigate the regulatory proteins upstream of REV1. Targeting REV1 could enhance the radiosensitivity in vivo, while this effect was not obvious in vitro. RNA sequencing combined with nontargeted metabolomics revealed that the difference result was related to metabolism, and that the expression of glycine, serine, and threonine (Gly/Ser/Thr) metabolism signaling pathways was downregulated following REV1 knockdown. LC-MS/MS demonstrated that REV1 knockdown results in reduced levels of these three amino acids and that cystathionine γ-lyase (CTH) was the key to its function. REV1 enhances the interaction of CTH with the E3 ubiquitin ligase Rad18 and promotes ubiquitination degradation of CTH by Rad18. Screening of the ubiquitination compound library revealed that the ubiquitin-specific peptidase 9 X-linked (USP9X) is the upstream regulatory protein of REV1 by the ubiquitin-proteasome system, which remodels the intracellular Gly/Ser/Thr metabolism. USP9X mediates the deubiquitination of REV1, and aberrantly expressed REV1 acts as a scaffolding protein to assist Rad18 in interacting with CTH, promoting the ubiquitination and degradation of CTH and inducing remodeling of the Gly/Ser/Thr metabolism, which leads to radioresistance. A novel inhibitor of REV1, JH-RE-06, was shown to enhance lung cancer cell radiosensitivity, with good prospects for clinical translation.

BACKGROUND:Immuno-chemotherapy has demonstrated significant anti-tumor effects in patients with resectable nonsmall cell lung cancer (NSCLC). Additionally, for patients initially diagnosed with unresectable stage III NSCLC, induction immuno-chemotherapy may achieve tumor downstaging, enabling conversion to resectable disease allowing for by R0 resection. This study aimed to assess the effectiveness and safety of induction immuno-chemotherapy followed by conversion surgery in unresectable stage III NSCLC. PATIENTS AND METHODS:A total of 113 patients with unresectable stage Ⅲ NSCLC who received induction immuno-chemotherapy at three institutions in China from March 2019 to April 2022 were retrospectively identified. After 2-4 cycles of immuno-chemotherapy, a multisiciplinary team (MDT) reassessed the tumor response and resectability in each case. Surgical resection was performed for patients who achieved tumor downstaging to resectable disease. Surgical and oncological outcomes of the patients were analyzed. RESULTS:Of the 113 patients treated with immuno-chemotherapy, 79 (69.9%) achieved conversion to resectable state and underwent surgery. Surgical procedures included lobectomy in 55 (69.6%) patients, sleeve lobectomy in 14 (17.7%) patients, bilobectomy in 6 (7.6%) patients, and pneumonectomy in 4 (5.1%) patients, achieving an R0 resection rate of 98.7% (78/79). No surgical-related 30-day or 90-day mortalities were recorded, although 17 patients (21.5%) experienced postoperative complications. In terms of pathological response, 44 (55.7%) patients achieved major pathologic response and 25 (31.6%) patients achieved complete pathologic response. Median progression-free survival (PFS) and overall survival (OS) was not reached. The 12- and 24-month PFS rates were 82.3% and 72.2%, while OS rates were 94.9% and 84.5%, respectively. CONCLUSION:Conversion surgery following immuno-chemotherapy is feasible and safe, yielding promising pathological responses and favorable survival outcomes for patients with unresectable stage III NSCLC.

KDM4C, which is a histone lysine demethylase, has been proposed to participate in the malignant transformation and progression of several types of cancer. However, its roles in hepatocellular carcinoma (HCC) remain poorly understood. Here, we find that KDM4C protein expression is increased in HCC and promotes HCC cell growth, proliferation and migration. Furthermore, we provide evidence that depletion of KDM4C leads to a defective G2/M checkpoint, increases radiation-induced DNA damage, impairs DNA repair and enhances radiosensitivity in HCC cells. Using RNA sequencing, we identify that the chemokine CXCL2 is a downstream effector of KDM4C. KDM4C knockdown increases the binding of H3K36me3 to the promoter of CXCL2, thus upregulating CXCL2 expression and promoting CXCL2 secretion in HCC cells. Importantly, the observed effects of KDM4C depletion in HCC cells can be partially rescued by CXCL2 silencing. Thus, our findings reveal that KDM4C is involved in cell migration and radiosensitivity by modulating CXCL2 transcription, indicating that KDM4C may be a potential therapeutic target in HCC.

Purpose Tumor radiation resistance is the main obstacle to effective radiation therapy for patients with hepatocellular carcinoma (HCC). We identified the role of urea cycle key enzyme carbamoyl phosphate synthetase 1 (CPS1) in radioresistance of HCC and explored its mechanism, aiming to provide a novel radiosensitization strategy for the CPS1-deficiency HCC subtype. Methods and Materials The expression of CPS1 was measured by western blot and immunohistochemistry. Cell growth assay, EdU assay, cell apoptosis assay, cell cycle assay, clone formation assay, and subcutaneous tumor assay were performed to explore the relationship between CPS1 and radioresistance of HCC cells. Lipid metabonomic analysis was used for investigating the effects of CPS1 on lipid synthesis of HCC cells. RNA sequencing and coimmunoprecipitation assay were carried out to reveal the mechanism of CPS1 participating in the regulation of HCC radiation therapy resistance. Furthermore, 10074-G5, the specific inhibitor of c-Myc, was administered to HCC cells to investigate the role of c-Myc in CPS1-deficiency HCC cells. Results We found that urea cycle key enzyme CPS1 was frequently lower in human HCC samples and positively associated with the patient's prognosis. Functionally, the present study proved that CPS1 depletion could accelerate the development of HCC and induce radiation resistance of HCC in vitro and in vivo, and deficiency of CPS1 promoted the synthesis of some lipid molecules. Regarding the mechanism, we uncovered that inhibition of CPS1 upregulated CyclinA2 and CyclinD1 by stabilizing oncoprotein c-Myc at the posttranscriptional level and generated radioresistance of HCC cells. Moreover, inactivation of c-Myc using 10074-G5, a specific c-Myc inhibitor, could partially attenuate the proliferation and radioresistance induced by depletion of CPS1. Conclusions Our results recapitulated that silencing CPS1 could promote HCC progression and radioresistance via c-Myc stability mediated by the ubiquitin-proteasome system, suggesting that targeting c-Myc in CPS1-deficiency HCC subtype may be a valuable radiosensitization strategy in the treatment of HCC.

Cancer cells inevitably develop radioresistance during lung adenocarcinoma radiotherapy.However, the mechanisms are incompletely clarified.In this study, we show that FIBP protein expression in lung adenocarcinoma tissues is upregulated and associated with worse overall survival.Functionally, we find that depletion of FIBP inhibits lung adenocarcinoma progression and radioresistance in vitro and in vivo.Moreover, we uncover that FIBP interacts with STAT3 to enhance its transcriptional activity, thereby inducing the expression of the downstream target gene EME1.Importantly, we demonstrate that the biological effects of FIBP are partially dependent on EME1 in lung adenocarcinoma.Our work reveals that FIBP modulates the STAT3/EME1 axis to drive lung cancer progression and radioresistance, indicating that targeting FIBP may be a novel intervention strategy for lung adenocarcinoma radiotherapy.

BACKGROUND:Pemetrexed plus platinum doublet chemotherapy regimen remains to be the standard first-line treatment for lung adenocarcinoma patients. However, few biomarkers can be used to identify potential beneficiaries with maximal efficacy and minimal toxicity. This study aimed to explore potential biomarker models predictive of efficacy and toxicity after pemetrexed plus platinum chemotherapy based on metabolomics profiling. METHODS:A total of 144 patients who received at least two cycles of pemetrexed plus platinum chemotherapy were enroled in the study. Serum samples were collected before initial treatment to perform metabolomics profiling analysis. Logistic regression analysis was performed to establish prediction models. RESULTS:157 metabolites were found to be differentially expressed between the response group and the nonresponse group. A panel of Phosphatidylserine 20:4/20:1, Sphingomyelin d18:1/18:0, and Phosphatidic Acid 18:1/20:0 could predict pemetrexed and platinum chemotherapy response with an Area Under the Receiver Operating Characteristic curve (AUROC) of 0.7968. 76 metabolites were associated with hematological toxicity of pemetrexed plus platinum chemotherapy. A panel incorporating triglyceride 14:0/22:3/22:5, 3-(3-Hydroxyphenyl) Propionate Acid, and Carnitine C18:0 was the best predictive ability of hematological toxicity with an AUROC of 0.7954. 54 differential expressed metabolites were found to be associated with hepatotoxicity of pemetrexed plus platinum chemotherapy. A model incorporating stearidonic acid, Thromboxane B3, l-Homocitrulline, and phosphoinositide 20:3/18:0 showed the best predictive ability of hepatotoxicity with an AUROC of 0.8186. CONCLUSIONS:This study established effective and convenient models that can predict the efficacy and toxicity of pemetrexed plus platinum chemotherapy in lung adenocarcinoma patients before treatment delivery.

BackgroundChemoradiotherapy‐induced PD‐L1 upregulation leads to therapeutic resistance and treatment failure. The PD‐1/PD‐L1 blocking antibodies sensitize cancers to chemoradiotherapy by blocking extracellular PD‐1 and PD‐L1 binding without affecting the oncogenic function of intracellular PD‐L1. Reversing the chemoradiation‐induced PD‐L1 expression could provide a new strategy to achieve a greater anti‐tumour effect of chemoradiotherapy. Here, we aimed to identify candidate small molecular inhibitors that might boost the anti‐tumour immunity of chemoradiotherapy by decreasing treatment‐induced PD‐L1 expression in non‐small cell lung cancer (NSCLC).MethodsA drug array was used to recognize compounds that can suppress the cisplatin‐induced and radiation‐induced PD‐L1 expression in NSCLC via the flow cytometry‐based assay. We examined whether and how targeting bromodomain containing 4 (BRD4) inhibits chemoradiation‐induced PD‐L1 expression and evaluated the effect of BRD4 inhibition and chemoradiation combination in vivo.ResultsBRD4 inhibitors JQ1 and ARV‐771 were identified as the most promising drugs both in the cisplatin and radiation screening projects in two NSCLC cell lines. Targeting BRD4 was supposed to block chemoradiotherapy inducible PD‐L1 expression by disrupting the recruitment of BRD4‐IRF1 complex to PD‐L1 promoter. A positive correlation between BRD4 and PD‐L1 expression was observed in human NSCLC tissues. Moreover, BRD4 inhibition synergized with chemoradiotherapy and PD‐1 blockade to show a robust anti‐tumour immunity dependent on CD8+ T cell through limiting chemoradiation‐induced tumour cell surface PD‐L1 upregulation in vivo. Notably, the BRD4‐targeted combinatory treatments did not show increased toxicities.ConclusionThe data showed that BRD4‐targeted therapy synergized with chemoradiotherapy and anti‐PD‐1 antibody by boosting anti‐tumour immunity in NSCLC.

Background Although immune checkpoint blockade (ICB) has been proven to achieve a persistent therapeutic response in various tumor types, only 20%–40% of patients benefit from this treatment. Radiotherapy (RT) can enhance tumor immunogenicity and improve the ICB response, but the outcome achieved by combining these two modalities remains clinically unsatisfactory. We previously uncovered that lysine-specific demethylase 4C (KDM4C) is a regulator of radiosensitivity in lung cancer. However, the role of KDM4C in antitumor immunity has not yet been investigated. Methods Infiltrating immune cells in our mouse tumor model were screened by flow cytometry. An in vivo subcutaneous transplanted tumor model and in vitro conditioned culture model were constructed to detect the quantitative and functional changes in CD8+ T cells. RNA sequencing and chromatin immunoprecipitation-PCR assays were used to explore the downstream regulatory mechanism of KDM4C in antitumor immunity. A C57BL/6 mouse tumor model was developed to evaluate the efficacy and safety of a triple therapy (the KDM4C-specific inhibitor SD70 plus RT and an anti-PD-L1 antibody) in lung cancer in vivo. Results Genetical or pharmacological inhibition of KDM4C specifically increased CD8+ T cell infiltration; promoted the proliferation, migration and activation of CD8+ T cells; and alleviated CD8+ T cell exhaustion in mouse tumor tissues. Mechanistically, KDM4C inhibition increased the binding of H3K36me3 to the CXCL10 promoter region, thus inducing CXCL10 transcription and enhancing the CD8+ T cell mediated antitumor immune response. More importantly, among the tested regimens, the triple therapy achieved the best therapeutic efficacy with tolerable toxicity in lung cancer. Conclusions Our data reveal a crucial role for KDM4C in antitumor immunity in lung cancer and indicate that targeting KDM4C in combination with radioimmunotherapy might be a promising synergistic strategy in lung cancer.

Radioresistance is regarded as the main cause of local recurrence and distant metastasis in non-small cell lung cancer. However, the underlying mechanisms of radioresistance remains incompletely understood. In this study, we find that the arginine methyltransferase PRMT5 interacts with and methylates Mxi1, which promotes the binding of the β-Trcp ligase to Mxi1, facilitating the ubiquitination and degradation of Mxi1 in lung cancer. Furthermore, genetic blockade of PRMT5 impairs DNA damage repair and enhances lung cancer radiosensitivity in vitro and in vivo, and these phenotypes are partially reversed by Mxi1 silencing. More importantly, pharmacological inhibition of PRMT5 with the specific inhibitor EPZ015666 leads to extraordinary radiosensitization in vitro and in vivo in lung cancer. Altogether, our data indicate that PRMT5 methylates and destabilizes Mxi1 to confer radioresistance, suggesting that PRMT5 may be a promising radiosensitization target in non-small cell lung cancer.

Radioresistance is regarded as the main barrier to effective radiotherapy in lung cancer. However, the underlying mechanisms of radioresistance remain elusive. Here, we show that lysine-specific demethylase 4C (KDM4C) is overexpressed and correlated with poor prognosis in lung cancer patients. We provide evidence that genetical or pharmacological inhibition of KDM4C impairs tumorigenesis and radioresistance in lung cancer in vitro and in vivo. Moreover, we uncover that KDM4C upregulates TGF-β2 expression by directly reducing H3K9me3 level at the TGF-β2 promoter and then activates Smad/ATM/Chk2 signaling to confer radioresistance in lung cancer. Using tandem affinity purification technology, we further identify deubiquitinase USP9X as a critical binding partner that deubiquitinates and stabilizes KDM4C. More importantly, depletion of USP9X impairs TGF-β2/Smad signaling and radioresistance by destabilizing KDM4C in lung cancer cells. Thus, our findings demonstrate that USP9X-mediated KDM4C deubiquitination activates TGF-β2/Smad signaling to promote radioresistance, suggesting that targeting KDM4C may be a promising radiosensitization strategy in the treatment of lung cancer.

Radiotherapy kills tumor cells by radiation-induced DNA double-strand breaks (DSB), however, abnormal DSB repair in tumor cells often leads to radioresistance, in which epigenetics plays an important role. Targeting aberrant epigenetic markers may be a potential means of cancer radiosensitization, but the clinical application of the combination of epigenetic drugs and radiotherapy requires further investigation. This article reviews the latest research progress the role of epigenetics in the repair of radiation-induced DNA damage in tumors.

Background: Recent studies have demonstrated benefits from adjuvant tyrosine-kinase inhibitors (TKIs) compared with chemotherapy in non-small cell lung cancer. We launched a multi-center retrospective study to evaluate the efficacy and toxicity of adjuvant TKIs with or without chemotherapy in epidermal growth factor receptor (EGFR)-mutant stage III-pN2 lung adenocarcinoma. Methods: Two hundred and seventy-four consecutive cases with stage III-pN2 lung adenocarcinoma and complete resection have been investigated. Clinic-pathologic characteristics, adjuvant treatments, long-term survivals, and toxicities were documented. Risk factors of distant metastasis-free survival (DMFS), disease-free survival (DFS), and overall survival (OS) were evaluated. Results: There were 52 (19.0%) patients treated with adjuvant TKIs alone, 199 (72.6%) with adjuvant chemotherapy alone, and 23 (8.4%) with both. After a median follow-up time of 29 months, the two-year DMFS, DFS, and OS was 61.2%, 54.1%, and 91.2%, respectively. According to univariable analyses, the risk factors were lymphovascular invasion (p < 0.001), extranodal extension (p = 0.005), and adjuvant systemic therapy (p = 0.006) for DMFS, EGFR mutation type (p = 0.025), lymphovascular invasion (p = 0.013), extranodal extension (p = 0.004), and adjuvant systemic therapy (p < 0.001) for DFS, and EGFR mutation type (p < 0.001) for OS. Multivariable analyses indicated that the independent prognostic factors were adjuvant systemic therapy (TKIs vs. TKIs+chemotherapy, Harzard ratio (HR) = 0.40; p = 0.036; TKIs vs. chemotherapy, HR = 0.38; p = 0.004), lymphovascular invasion (yes vs. no, HR = 2.22; p = 0.001) for DMFS, and adjuvant systemic therapy (TKIs vs. TKIs+chemotherapy, HR = 0.42; p = 0.034; TKIs vs. chemotherapy, HR = 0.33; p < 0.001) for DFS. No significant difference was found in the incidence of Grade 3–4 toxicities between groups (p = 0.445). Conclusions: Adjuvant TKIs might be a beneficial choice compared with adjuvant chemotherapy or combination systemic treatments.