Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are currently the first-line standard of care for patients with non-small cell lung cancer (NSCLC) that harbor EGFR mutations. Nevertheless, resistance to EGFR-TKIs is inevitable. In recent years, although immune checkpoint inhibitors (ICIs) have significantly shifted the treatment paradigm in advanced NSCLC without driver mutation, clinical benefits of these agents are limited in patients with EGFR-mutated NSCLC. Compared with wild-type tumors, tumors with EGFR mutations show more heterogeneity in the expression level of programmed cell death ligand 1 (PD-L1), tumor mutational burden (TMB), and other tumor microenvironment (TME) characteristics. Whether ICIs are suitable for NSCLC patients with EGFR mutations is still worth exploring. In this review, we summarized the clinical data with regard to the efficacy of ICIs in patients with EGFR-mutated NSCLC and deciphered the unique TME in EGFR-mutated NSCLC.
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Humans ; Carcinoma, Non-Small-Cell Lung/genetics* ; Lung Neoplasms/genetics* ; ErbB Receptors/metabolism* ; Immunotherapy ; Mutation ; B7-H1 Antigen/genetics* ; Protein Kinase Inhibitors/pharmacology* ; Tumor Microenvironment

OBJECTIVE: To investigate the effect and possible mechanism of hydroxysafflor yellow A (HSYA) on human immortalized keratinocyte cell proliferation and migration. METHODS: HaCaT cells were treated with HSYA. Cell proliferation was detected by the cell counting kit-8 assay, and cell migration was measured using wound healing assay and Transwell migration assay. The mRNA and protein expression levels of heparin-binding epidermal growth factor (EGF)-like growth factor (HBEGF), EGF receptor (EGFR), phosphatidylinositol 3-kinase (PI3K), protein kinase B (AKT), mammalian target of rapamycin (mTOR), and hypoxia-inducible factor-1α (HIF-1α) were detected by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot, respectively. Circ_0084443-overexpressing HaCaT cells and empty plasmid HaCaT cells were constructed using the lentiviral stable transfection and treated with HSYA. The expression of circ_0084443 was detected by qRT-PCR. RESULTS: HSYA (800 µmol/L) significantly promoted HaCaT cell proliferation and migration (P<0.05 or P<0.01). It also increased the mRNA and protein expression levels of HBEGF, EGFR, PI3K, AKT, mTOR and HIF-1α, and increased the phosphorylation levels of PI3K and AKT (P<0.05 or P<0.01). Furthermore, HSYA promoted HaCaT cell proliferation and migration via the HBEGF/EGFR and PI3K/AKT/mTOR signaling pathways (P<0.01). Circ_0084443 attenuated the mRNA expression levels of HBEGF, EGFR, PI3K, AKT, mTOR and HIF-1α (P<0.05). HSYA inhibited the circ_0084443 expression, further antagonized the inhibition of circ_0084443 on HBEGF, EGFR, PI3K, AKT, mTOR and HIF-1α, and promoted the proliferation of circ_0084443-overexpressing HaCaT cells (P<0.05 or P<0.01). However, HSYA could not influence the inhibitory effect of circ_0084443 on HaCaT cell migration (P>0.05). CONCLUSION HSYA played an accelerative role in HaCaT cell proliferation and migration, which may be attributable to activating HBEGF/EGFR and PI3K/AKT signaling pathways, and had a particular inhibitory effect on the keratinocyte negative regulator circ_0084443.
Humans ; Proto-Oncogene Proteins c-akt/metabolism* ; Phosphatidylinositol 3-Kinase ; Phosphatidylinositol 3-Kinases/metabolism* ; ErbB Receptors/genetics* ; TOR Serine-Threonine Kinases/metabolism* ; Cell Proliferation ; RNA, Messenger/genetics* ; Cell Movement ; Cell Line, Tumor ; Chalcone/analogs & derivatives* ; Quinones

OBJECTIVE: To determine whether monotropein has an anticancer effect and explore its potential mechanisms against colorectal cancer (CRC) through network pharmacology and molecular docking combined with experimental verification. METHODS: Network pharmacology and molecular docking were used to predict potential targets of monotropein against CRC. Cell counting kit assay, plate monoclonal assay and microscopic observation were used to investigate the antiproliferative effects of monotropein on CRC cells HCT116, HT29 and LoVo. Flow cytometry and scratch assay were used to analyze apoptosis and cell cycle, as well as cell migration, respectively in HCT116, HT29, and LoVo cells. Western blotting was used to detect the expression of proteins related to apoptosis, cell cycle, and cell migration, and the expression of proteins key to the Akt pathway. RESULTS: The Gene Ontology and Reactome enrichment analyses indicated that the anticancer potential of monotropein against CRC might be involved in multiple cancer-related signaling pathways. Among these pathways, RAC-beta serine/threonine-protein kinase (Akt1, Akt2), cyclin-dependent kinase 6 (CDK6), matrix metalloproteinase-9 (MMP9), epidermal growth factor receptor (EGFR), cell division control protein 42 homolog (CDC42) were shown as the potential anticancer targets of monotropein against CRC. Molecular docking suggested that monotropein may interact with the 6 targets (Akt1, Akt2, CDK6, MMP9, EGFR, CDC42). Subsequently, cell activity of HCT116, HT29 and LoVo cell lines were significantly suppressed by monotropein (P<0.05). Furthermore, our research revealed that monotropein induced cell apoptosis by inhibiting Bcl-2 and increasing Bax, induced G₁-S cycle arrest in colorectal cancer by decreasing the expressions of CyclinD1, CDK4 and CDK6, inhibited cell migration by suppressing the expressions of CDC42 and MMP9 (P<0.05), and might play an anticancer role through Akt signaling pathway. CONCLUSION Monotropein exerts its antitumor effects primarily by arresting the cell cycle, causing cell apoptosis, and inhibiting cell migration. This indicates a high potential for developing novel medication for treating CRC.
Humans ; Proto-Oncogene Proteins c-akt/metabolism* ; Cell Proliferation ; Matrix Metalloproteinase 9 ; Molecular Docking Simulation ; Cell Cycle ; ErbB Receptors ; Apoptosis ; Colorectal Neoplasms/pathology* ; Cell Line, Tumor

BACKGROUND: Lung cancer prevails and induces high mortality around the world. This study provided real-world information on the evolution of clinicopathological profiles and survival outcomes of lung cancer, and provided survival information within stage I subtypes. METHODS: Patients pathologically confirmed with lung cancer between January 2009 and December 2018 were identified with complete clinicopathological information, molecular testing results, and follow-up data. Shifts in clinical characteristics were evaluated using χ2 tests. Overall survival (OS) was calculated through the Kaplan-Meier method. RESULTS: A total of 26,226 eligible lung cancer patients were included, among whom 62.55% were male and 52.89% were smokers. Non-smokers and elderly patients took increasingly larger proportions in the whole patient population. The proportion of adenocarcinoma increased from 51.63% to 71.80%, while that of squamous carcinoma decreased from 28.43% to 17.60%. Gene mutations including EGFR (52.14%), KRAS (12.14%), and ALK (8.12%) were observed. Female, younger, non-smoking, adenocarcinoma patients and those with mutated EGFR had better survival prognoses. Importantly, this study validated that early detection of early-stage lung cancer patients had contributed to pronounced survival benefits during the decade. Patients with stage I lung cancer, accounted for an increasingly considerable proportion, increasing from 15.28% to 40.25%, coinciding with the surgery rate increasing from 38.14% to 54.25%. Overall, period survival analyses found that 42.69% of patients survived 5 years, and stage I patients had a 5-year OS of 84.20%. Compared with that in 2009-2013, the prognosis of stage I patients in 2014-2018 was dramatically better, with 5-year OS increasing from 73.26% to 87.68%. Regarding the specific survival benefits among stage I patients, the 5-year survival rates were 95.28%, 93.25%, 82.08%, and 74.50% for stage IA1, IA2, IA3, and IB, respectively, far more promising than previous reports. CONCLUSIONS Crucial clinical and pathological changes have been observed in the past decade. Notably, the increased incidence of stage I lung cancer coincided with an improved prognosis, indicating actual benefits of early detection and management of lung cancer.
Humans ; Male ; Female ; Aged ; Lung Neoplasms/genetics* ; Adenocarcinoma/pathology* ; Prognosis ; Survival Rate ; Mutation ; ErbB Receptors/genetics* ; Neoplasm Staging ; Retrospective Studies

This study aimed to investigate the mechanism of resveratrol(RES) combined with irinotecan(IRI) in the treatment of colorectal cancer(CRC). The targets of RES, IRI, and CRC were obtained from databases, and the targets of RES combined with IRI in the treatment of CRC were acquired by Venn diagram. The protein functional cluster analysis, GO and KEGG enrichment analyses were performed. In addition, the protein-protein interaction(PPI) network was constructed. The core target genes were screened out and the target-signaling pathway network was set up. IGEMDOCK was used to dock the core target gene molecules. Besides, the relationship between the expression level of key target genes and the prognosis and immune infiltration of CRC was analyzed. Based on the in vitro cell experiment, the molecular mechanism of RES combined with IRI in the treatment of CRC was explored and analyzed. According to the results, 63 potential targets of RES combined with IRI were obtained for CRC treatment. Furthermore, cluster analysis revealed that protein functions included 23% transmembrane signal receptors, 22% protein modifying enzymes, and 14% metabolite converting enzymes. GO analysis indicated that BPs were mainly concentrated in protein autophosphorylation, CCs in receptor complex and plasma membrane, and MFs in transmembrane receptor protein tyrosine kinase activity. Moreover, KEGG signaling pathways were mainly enriched in central carbon metabolism in cancer. The key targets of RES combined with IRI in the treatment of CRC were PIK3CA, EGFR, and IGF1R, all of which were significantly positively correlated with the immune infiltration of CRC. As shown by the molecular docking results, PIK3CA had the most stable binding with RES and IRI. Compared with the results in the control group, the proliferation ability and EGFR protein expression of CRC cells in the RES-treated group, the IRI-treated group, and the RES+IRI treated group significantly decreased. Moreover, the cell proliferation ability and EGFR protein expression level of CRC cells in the RES+IRI treated group were remarkably lower than those in the IRI-treated group. In conclusion, PIK3CA, EGFR, and IGF1R are the key targets of RES combined with IRI in CRC treatment. In addition, RES can inhibit the proliferation of CRC cells and improve IRI chemoresistance by downregulating the EGFR signaling pathway.
Humans ; Irinotecan ; Colorectal Neoplasms/genetics* ; Resveratrol ; Molecular Docking Simulation ; ErbB Receptors/genetics*

BACKGROUND: Epidermal growth factor receptor (EGFR) gene mutations are the most common driver mutations in non-small cell lung cancer (NSCLC). To prolong the survival of the patients, EGFR tyrosine kinase inhibitors (TKIs) resistance in NSCLC is a major challenge that needs to be addressed urgently, and this study focuses on investigating the mechanism of cigarette smoke (CS) induced Gefitinib resistance in NSCLC. METHODS: PC-9 and A549 cells were cultured in vitro and treated with 1 µmol/L Gefitinib for 4 h and 10% cigarette smoke extract (CSE) for 48 h. Western blot was used to detect Sirtuin 3 (Sirt3) and superoxide dismutase 2 (SOD2) protein expressions; DCFH-DA probe was used to detect intracellular reactive oxygen species (ROS); CCK-8 kit was used to detect cell activity, and EdU was used to detect cell proliferation ability. Sirt3 overexpression plasmid (OV-Sirt3) was transfected in PC-9 and A549 cells and treated with 1 µmol/L Gefitinib for 4 h and 10% CSE for 48 h after N-acetylcysteine (NAC) action. The expressions of Sirt3 and SOD2 were detected by Western blot; the ROS level in the cells was detected by DCFH-DA probe, and the cell activity was detected by CCK-8. RESULTS: CSE induced an increase in the 50% inhibitory concentration (IC50) of both PC-9 and A549 cells to Gefitinib (P<0.01) and enhanced the proliferation of PC-9 and A549 cells, suggesting that CS induced Gefitinib resistance in NSCLC. ROS was involved in CSE-induced Gefitinib resistance (P<0.05). CSE induced low expressions of Sirt3 and SOD2 (P<0.01), and Sirt3/SOD2 was associated with poor prognosis in lung cancer patients (P<0.05). OV-Sirt3 in PC-9 and A549 cells reversed CSE-induced Gefitinib resistance (P<0.05) and significantly reduced ROS production. NAC reversed CSE-induced Gefitinib resistance in PC-9 and A549 cells (P<0.05). CONCLUSIONS The ROS/Sirt3/SOD2 pathway is involved in CS-induced Gefitinib resistance in NSCLC.
Humans ; Gefitinib/therapeutic use* ; Carcinoma, Non-Small-Cell Lung/metabolism* ; Sirtuin 3/therapeutic use* ; Lung Neoplasms/metabolism* ; Reactive Oxygen Species/therapeutic use* ; Antineoplastic Agents/therapeutic use* ; Cigarette Smoking ; Sincalide/therapeutic use* ; ErbB Receptors/metabolism* ; Drug Resistance, Neoplasm/genetics* ; Cell Line, Tumor

With the development of precision diagnosis and treatment for non-small cell lung cancer (NSCLC), the epidermal growth factor receptor (EGFR) exon 20 insertion (ex20ins) mutations, as a rare subset of EGFR mutaions, have gradually attracted attention recently. The heterogeneity of EGFR ex20ins mutations is very high, different variants have different clinical benefits, and the prognosis is extremely poor. The available traditional treatment outcomes are poor in patients with EGFR ex20ins positive NSCLC and polymerase chain reaction (PCR) tests would miss aprocimately 50% of the variants. Therefore, high attention should be paid to EGFR ex20ins positive NSCLC during the clinical practice. The expert panel has formed a consensus on the standardized clinical diagnosis and treatment of EGFR ex20ins mutation NSCLC through reference to literature and clinical data, and combined with the experts' own clinical experience, the consensus recommendations including clinicopathologic characteristics, therapies, testing methods and recent relevant clinical trials for NSCLC patients with EGFR ex20ins mutation, in order to provide medication reference for clinical physicians at all levels.
Humans ; Carcinoma, Non-Small-Cell Lung/therapy* ; Consensus ; ErbB Receptors/genetics* ; Exons ; Lung Neoplasms/therapy* ; Mutagenesis, Insertional

With the development of precision medicine for lung cancer, targeted therapy has greatly improved the survival and prognosis of patients with advanced non-small cell lung cancer (NSCLC), but the occurrence of acquired drug resistance ultimately leads to patients with no targeted drugs available and no standard treatment options for this group of patients afterwards. The emergence of immune checkpoint inhibitors (ICIs) has revolutionized the treatment of advanced NSCLC. However, due to the unique features of NSCLC with epidermal growth factor receptor (EGFR) mutation, such as immunosuppressive tumor microenvironment (TME), single ICIs treatment has limited clinical benefits in NSCLC patients with EGFR mutation, and the combination of ICIs with chemotherapy and/or targeted therapies is the trend. This review further discusses potential subpopulations with EGFR mutations that may benefit from ICIs treatment, and analyzes how decisions can be made in the era of combined immunotherapy to maximize the efficacy of ICIs treatment in EGFR mutation targeted therapy for NSCLC patients with drug resistance, with the aim of achieving individualized treatment.
Humans ; Carcinoma, Non-Small-Cell Lung/genetics* ; Immune Checkpoint Inhibitors ; Lung Neoplasms/genetics* ; Mutation ; ErbB Receptors/genetics* ; Tumor Microenvironment

CUDC-101, an effective and multi-target inhibitor of epidermal growth factor receptor (EGFR), histone deacetylase (HDAC), and human epidermal growth factor receptor 2 (HER2), has been reported to inhibit many kinds of cancers, such as acute promyelocytic leukemia and non-Hodgkin's lymphoma. However, no studies have yet investigated whether CUDC-101 is effective against myeloma. Herein, we proved that CUDC-101 effectively inhibits the proliferation of multiple myeloma (MM) cell lines and induces cell apoptosis in a time- and dose-dependent manner. Moreover, CUDC-101 markedly blocked the signaling pathway of EGFR/phosphoinositide-3-kinase (PI3K) and HDAC, and regulated the cell cycle G2/M arrest. Moreover, we revealed through in vivo experiment that CUDC-101 is a potent anti-myeloma drug. Bortezomib is one of the important drugs in MM treatment, and we investigated whether CUDC-101 has a synergistic or additive effect with bortezomib. The results showed that this drug combination had a synergistic anti-myeloma effect by inducing G2/M phase blockade. Collectively, our findings revealed that CUDC-101 could act on its own or in conjunction with bortezomib, which provides insights into exploring new strategies for MM treatment.
Humans ; Antineoplastic Agents/therapeutic use* ; Apoptosis ; Bortezomib/pharmacology* ; Cell Line, Tumor ; Cell Proliferation ; ErbB Receptors/antagonists & inhibitors* ; G2 Phase Cell Cycle Checkpoints ; Histone Deacetylase Inhibitors/pharmacology* ; Histone Deacetylases/metabolism* ; M Cells ; Multiple Myeloma/drug therapy*

Humans ; Protein-Tyrosine Kinases/genetics* ; Proto-Oncogene Proteins/genetics* ; Lung Neoplasms/pathology* ; Mutation ; ErbB Receptors/genetics* ; Oncogene Proteins, Fusion/genetics* ; Gene Rearrangement