Progress of Immunotherapy in EGFR-mutated Advanced Non-small Cell Lung Cancer / 中国肺癌杂志

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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Network pharmacology and molecular docking reveal the mechanism of resveratrol in oral squamous cell carcinoma treatment / 口腔疾病防治

Objective@#To explore the molecular mechanism of resveratrol (RES) in the treatment of oral squamous cell carcinoma (OSCC) through the use of biological information methods such as network pharmacology and molecular docking and to provide a theoretical reference for the clinical application of RES in the treatment of OSCC.@*Methods@#The Swiss Target Prediction(http://www.swisstargetprediction.ch), SEA (http://sea.bkslab.org)database, and Pharm mapper database(http://lilab-ecust.cn) were used to retrieve RES-related targets, and the DISGENET (www.disgenet.org), OMIM (https://omim.org) and GeneCards (https://www.genecards.org) databases were used to screen OSCC disease targets. The intersection of drugs and disease targets was determined, and Cytoscape 3.7.2 software was used to construct a "drug-diseasetarget pathway" network. The Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database was used to construct a target protein interaction network, and the DAVID database was used for enrichment analysis of key proteins. Finally, molecular docking validation of key proteins was performed using AutoDock and PyMOL. The enrichment analysis and molecular docking results were integrated to predict the possible molecular mechanisms of RES treatment in OSCC; western blot was used to determine the effect of resveratrol at different concentrations (50, 100) μmol/L on the expression of Src tyrosine kinase (SRC), epidermal growth factor receptor (EGFR), estrogen receptor gene 1 (ESR1), and phosphatidylinositol 3 kinase/protein kinase B (PI3K/AKT) signaling pathway proteins in OSCC HSC-3 cells.@*Results@#A total of 243 targets of RES drugs and 6 094 targets of OSCC were identified. A total of 116 potential common targets were obtained by intersecting drugs with disease targets. These potential targets mainly participate in biological processes such as in vivo protein self-phosphorylation, peptide tyrosine phosphorylation, transmembrane receptor protein tyrosine kinase signaling pathway, and positive regulation of RNA polymerase Ⅱ promoter transcription, and they interfere with the PI3K/AKT signaling pathway to exert anti-OSCC effects. The docking results of resveratrol with OSCC molecules indicated that key targets, such as EGFR, ESR1, and SRC, have good binding activity. The results of cell-based experiments showed that resveratrol inhibited the protein expression of SRC, EGFR, ESR1, p-PI3K, and p-AKT in HSC-3 cells in a dose-dependent manner.@*Conclusion@#RES can inhibit the expression of its targets EGFR, ESR1, SRC, p-PI3K, and p-AKT in OSCC cells.

Hydroxysafflor Yellow A Promotes HaCaT Cell Proliferation and Migration by Regulating HBEGF/EGFR and PI3K/AKT Pathways and Circ_0084443 / 中国结合医学杂志

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.

Clinical application and progression of monoclonal antibodies targeting HER2 extracellular domain Ⅳ in breast cancer / 中国药房

Human epidermal growth factor receptor 2 （HER2）-positive breast cancer is aggressive and prone to metastasis，and the applications of HER2 agents have improved the prognosis of patients with HER2-positive breast cancer. Among the marketed HER2 agents，macromolecular monoclonal antibodies that target the extracellular domain Ⅳ of HER2 were the cornerstone drugs of HER2-positive breast cancer，including trastuzumab，inetetamab，and margetuximab. Trastuzumab is available for the full-line treatment of breast cancer with sufficient proof of evidence-based medicine，sufficient practical experience and controllable safety. Inetetamab and trastuzumab have similar efficacy and controllable safety in HER2-positive metastatic breast cancer and neoadjuvant/ adjuvant therapy. Margetuximab focuses on patients carrying the CD16A-158F allele，and is an option of posterior line treatment for advanced breast cancer. It is necessary to select the most suitable drugs clinically according to the specific condition of the patient.

Expression of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2/neu in gallbladder carcinoma in North Indian population

Background: Gallbladder carcinoma (GBC) although rare is most frequent malignant neoplasm of biliary tract system and sixth most common malignancy of digestive tract. GBC is more common in females and there are studies which show expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 neu (HER2/neu) in GBC suggesting possible molecules for targeted therapy, but results are inconsistent. Aims and Objectives: The aim of this study was to find out expression of ER, PR, and HER2/neu in GBC in North Indian population and their possible association with clinicopathological features. Materials and Methods: A total 59 resected cases of GBC diagnosed by histopathological examination were included in the study. Expression of ER, PR, and HER2/neu was accessed by immunohistochemistry method and correlated with various clinicopathological features. Results: ER expression was absent in all GBC cases. PR expression was present in only one case. Positive expression of HER2/neu was present in 13 (22%) cases, in which 12 cases were of conventional adenocarcinoma and one case was of papillary adenocarcinoma. Well and moderately differentiated tumor had significantly higher HER2/neu expression as compared to poorly differentiated tumors (P = 0.001). Pre-obese patients had significantly higher HER2/neu expression as compared to non-obese patients (P = 0.008). Conclusion: In our study, there was no expression of estrogen and PR in GBC in North Indian population. Although small in number, there is a subset of patients who overexpress HER2/neu receptor that may benefit from targeted therapy.

Research Progress on the Combination Therapy of EGFR-TKIs and Metformin in Acquired Resistance to EGFR-TKIs in Non-small Cell Lung Cancer / 中国肺癌杂志

Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) targeting EGFR are effective in EGFR mutation-positive non-small cell lung cancer (NSCLC) patients, but drug resistance is inevitable. With the application and expansion of individualized and combined therapy, more and more studies have shown that combined administration of Metformin effectively solves the problem of acquired drug resistance to EGFR-TKIs in clinical treatment and prolongs the survival of patients with NSCLC. EGFR-TKIs combined with Metformin is expected to be the treatment method of choice for NSCLC patients with EGFR-TKIs resistance. This paper intends to summarize the research progress of EGFR-TKIs combined with Metformin in the treatment of EGFR-TKIs acquired resistance in NSCLC, in order to provide a new idea for the treatment of NSCLC patients with acquired resistance to EGFR-TKIs.
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A Rare Case of Lung Adenocarcinoma with EGFR L833V/H835L Co-mutation and Literature Review / 中国肺癌杂志

Epidermal growth factor receptor (EGFR) mutations are the most common driver genes in the development of non-small cell lung cancer (NSCLC), of which mutations in exons 18-21 are frequent, especially the loss of exon 19 and exon 21 L858R mutation are the most frequent. Other rare gene mutations are rare. Simultaneous occurrence of two or more rare EGFR mutations are extremely rare in lung cancer, and the incidence of EGFR L833V/H835L rare gene compound mutations is very low, and there is little clinical data and evidence of relevant treatment methods. Some EGFR-tyrosine kinase inhibitors (EGFR-TKIs) are effective in treating lung cancer patients with rare gene mutations. In this article, we reported a case of NSCLC patient with a rare gene compound mutation EGFR L833V/H835L, who responded to Afatinib in combination with Anilotinib treatment well after 5 months of treatment, and computed tomography (CT) showed shrinkage of lung lesions. Meanwhile, we also compiled previously reported NSCLC patients with EGFR L833V/H835L rare gene compound mutation and summarized the characteristics of this group of patients and the effect of applying different kinds of EGFR-TKIs treatment.
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Construction and functional analysis of EGFRvIII CAR-T cells co-expressing IL-15 and CCL19 / 生物工程学报

The aim of this study was to investigate the functional characteristics and in vitro specific killing effect of EGFRvIII CAR-T cells co-expressing interleukin-15 and chemokine CCL19, in order to optimize the multiple functions of CAR-T cells and improve the therapeutic effect of CAR-T cells targeting EGFRvIII on glioblastoma (GBM). The recombinant lentivirus plasmid was obtained by genetic engineering, transfected into 293T cells to obtain lentivirus and infected T cells to obtain the fourth generation CAR-T cells targeting EGFRvIII (EGFRvIII-IL-15-CCL19 CAR-T). The expression rate of CAR molecules, proliferation, chemotactic ability, in vitro specific killing ability and anti-apoptotic ability of the fourth and second generation CAR-T cells (EGFRvIII CAR-T) were detected by flow cytometry, cell counter, chemotaxis chamber and apoptosis kit. The results showed that compared with EGFRvIII CAR-T cells, EGFRvIII-IL-15-CCL19 CAR-T cells successfully secreted IL-15 and CCL19, and had stronger proliferation, chemotactic ability and anti-apoptosis ability in vitro (all P < 0.05), while there was no significant difference in killing ability in vitro. Therefore, CAR-T cells targeting EGFRvIII and secreting IL-15 and CCL19 are expected to improve the therapeutic effect of glioblastoma and provide an experimental basis for clinical trials.

Consensus on the clinical use of CDK4/6 inhibitors for the treatment of hormone receptor-positive human epidermal growth factor receptor 2-negative breast cancer (2023 edition) / 中华肿瘤杂志

Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors have led transformative breakthrough of clinical therapy for hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER-2)-negative breast cancer patients. CDK4/6 inhibitors that have been marketed in China include Ribociclib, Palbociclib, Abemaciclib and Dalpiciclib. For HR-positive HER-2-negative locally advanced and metastatic breast cancer, CDK4/6 inhibitors combined with endocrine therapy have become standard regimen, which can prolong the survival of patients. In the adjuvant treatment stage of early breast cancer, CDK4/6 inhibitors have also achieved positive results and been approved for indications. At present, CDK4/6 inhibitors have been widely used in clinical practice in China. In order to further improve the standardized application of CDK4/6 inhibitors in China, the Breast Cancer Expert Committee of the National Center for Cancer Quality Control and the Professional Committee of Clinical Research of Cancer Drugs of the Chinese Anti-Cancer Association organized the related expert to update the consensus based on the "CDK4/6 inhibitor consensus on clinical application of in the treatment of hormone receptor positive human epidermal growth factor receptor 2 negative advanced breast cancer (2021 edition)" . The updated consensus systematically introduces the pharmacological characteristics, drug monitoring and adverse event management, etc., of CDK4/6 inhibitors to promote the accuracy of clinical decision-making with the ultimate goal to prolong the overall survival of patients and improve the quality of life.

Clinicopathological Characteristics and Therapeutic Effect of Patients with Non-small Cell Lung Cancer and Uncommon EGFR Mutations / 肿瘤防治研究

Objective To investigate the clinicopathological characteristics and treatment effect of patients with non-small cell lung cancer (NSCLC) and uncommon epidermal growth factor receptor (EGFR) gene mutations. Methods Real-time fluorescence quantitative PCR was used to detect the mutation of EGFR in 674 samples of patients with NSCLC.The correlation between uncommon EGFR mutations and clinicopathological characteristics was analyzed. Results The EGFR mutation rate was 47.92%, of which the incidence of uncommon EGFR mutations was 5.19%, showed the presence of ex18 G719 A/S/C (G719X)(1.63%), ex20ins (1.04%), ex21 L861Q (0.74%), and compound mutations (1.78%).Correlation analysis showed that uncommon EGFR mutations were more common in women, non-smokers, patients with high-medium differentiation and adenocarcinoma, and patients were more prone to brain and bone metastasis (all P < 0.05).NSCLC with uncommon EGFR mutations showed no significant differences in clinical and pathological features compared with those with common sensitive mutations (all P > 0.05).Follow-up information was available on 31 patients, with a median follow-up time of 10 months, of which 23 were in advanced stage.Among eight patients with G719X mutation in late stage, seven patients used EGFR tyrosine kinase inhibitor (EGFR TKIs)(five of them used afatinib) in the first line and had a median PFS of 12 months; one patient received chemotherapy with pemetrexed and carboplatin and had PFS of seven months, which was lower than that of the TKI group.Among four patients with L861Q mutation in late stage, one patient was untreated and the three remaining were treated with TKI in the first line and had a median PFS of eight months.The patient who was treated with afatinib and bevacizumab was still stable after 11 months of follow-up.Two patients with EGFR ex20ins in advanced stage were treated with chemotherapy and bevacizumab.Nine patients with compound mutations in advanced stage were treated with TKI; among which, five patients harboring T790M compound mutations were treated with third-generation TKI and had a median PFS of more than 10 months. Conclusion The correlation between specific uncommon EGFR mutation and clinical pathological characteristics varies.For advanced patients with uncommon EGFR mutations (except for ex20ins), TKI is generally chosen as the first-line clinical treatment.Afatinib is recommended for advanced NSCLC patients with G719X and L861Q mutations.Third-generation TKI has significant efficacy in patients with complex mutations containing T790M.

Visual analysis of tyrosine kinase inhibitors in HER2 positive breast cancer / 中国药房

OBJECTIVE To analyze the research status， hotspot and development trend of tyrosine kinase inhibitors （TKIs） in the treatment of human epidermal growth factor receptor 2 （HER2） positive breast cancer. METHODS The literature related to TKIs in the treatment of HER2 positive breast cancer were searched from the Web of Science core collection database； the author， country/region， institution， subject field， journal and keywords was visualized by CiteSpace 6.1.R3 software. RESULTS A total of 732 pieces of literature were included， and the number of literature published showed an increasing trend year by year. The number of literature published in the United States was the largest （center degree 0.10）， and the number of literature published in China ranked second （center degree 0.05）. The most published and cited authors were Crown from St. Vincent’s University Hospital in Australia and Slamon from University of California， Los Angeles in the United States； the institution with the highest number of literature was the University of Texas MD Anderson Cancer Center， and the journal with the highest number of literature was the Journal of Clinical Oncology. The research mainly focused on five aspects： HER2 positive breast cancer treatment drugs， TKIs receptor， TKIs mechanism of action， HER2 positive breast cancer brain metastasis， and TKIs clinical trials. The main frontier areas and development trends were the combination of TKIs with other drugs or therapies to enhance targeting and reduce toxic side effects. CONCLUSIONS The study of TKIs in the treatment of HER2 positive breast cancer has attracted the attention of scholars at home and abroad. Chinese scholars and research teams need to strengthen cooperation and communication in the future， and cooperation with other countries should be strengthened in terms of the efficacy and safety of TKIs alone and combined with other drugs in the treatment of HER2 positive breast cancer.

Anti-tumor Activity of Chinese Medicine Based on EGFR Signaling Pathway： A Review / 中国实验方剂学杂志

In China， malignant tumors have become the main cause of death. In the past half century， the incidence and mortality of malignant tumors have been on the rise， posing a threat to health of patients， and the burden of cancer has been increasing. At the moment， malignant tumors are mainly treated by surgery， radiotherapy， and cytotoxic drugs， which， however， have limitations and induce great adverse reactions. As biological technology and the research on tumor microenvironment， immunology， cell biology， and molecular biology advance， high-efficiency low-toxicity targeted therapy has attracted wide attention in the treatment of tumors. Epidermal growth factor receptor （EGFR） plays an important role in many cellular processes such as cell proliferation， survival， differentiation， migration， inflammation， and stromal homeostasis. EGFR promotes tumor growth， proliferation， and metastasis in a variety of ways. Chinese medicine has unique efficacy in the comprehensive treatment of malignant tumors. Through multiple components， multiple targets， and multiple pathways， it enhances the efficacy， reduces toxicity， prolongs life， and improves life quality in the treatment of tumors. Many Chinese medicines and their active components exert anti-tumor effect by inhibiting the EGFR signal transduction pathway. Through targeted inhibition of EGFR， Chinese medicine can promote the apoptosis and autophagy of tumor cells， suppress the proliferation and metastasis of tumor cells， and delay the progression of tumors. Thus， EGFR is a potential target for suppressing tumor. This paper summarizes the relationship between EGFR signal transduction pathway and tumor occurrence and development and analyzes the anti-tumor action mode and possible mechanisms of Chinese medicine and the active components by regulating EGFR signaling pathway， which is expected to provide a reference for clinical practice.

Pathological features and immune microenvironment in HER-2 intratumoral heterogeneous breast cancers / 中华肿瘤杂志

Objective: To observe the clinical pathology features, and immune microenvironment of HER-2 intratumoral heterogeneity breast cancer. Methods: Thirty cases of HER-2 intratumoral heterogeneous breast cancer were retrospectively analyzed in Tianjin Medical University Cancer Institute and Hospital from November 2017 to June 2020. HER-2 expression was detected by immunohistochemistry and verified by dual color silver-enhanced in-situ hybridization (D-SISH). HER-2 intratumoral positive and negative regions were divided. The pathological characteristics, subtype, and the level of tumor infiltrating lymphocytes (TILs) and the expression of programmed cell death-ligand 1 (PD-L1) were evaluated respectively. Results: The proportion of HER-2 positive cells of the breast cancer ranged from 10% to 90%. The pathological type was mainly invasive non-special typecarcinoma. Six cases presented different pathological types between HER-2 positive and negative regions. The HER-2-positive areas included 2 cases of carcinoma with apocrine differentiation, and the negative areas included 2 cases of invasive micropapillary carcinoma, 1 case of invasive papillary carcinoma, and 1 case of carcinoma with apocrine differentiation. In HER-2 positive regions, 17 cases were Luminal B and 13 cases were HER-2 overexpressed types. There were 22 cases of Luminal B and 8 cases of triple negative tumors in the HER-2 negative areas. The levels of TILs in HER-2 positive and negative areas accounted for 53.3% (16/30) and 26.7% (8/30), respectively, with a statistically significant difference (P=0.035). The positive expression of PD-L1 in HER-2 positive area and HER-2 negative area were 6 cases and 9 cases, respectively. Among 8 cases with HER-2 negative regions containing triple negative components, 4 cases were positive for PD-L1 expression. Conclusions: In the case of HER-2 intratumoral heterogeneity, it is necessary to pay attention to both HER-2 positive and negative regions, and evaluate subtype separately as far as possible. For HER-2 intratumoral heterogeneous breast cancer containing triple negative components, the treatment mode can be optimized by refining the intratumoral expression of PD-L1.

Effects of adjuvant trastuzumab on long-term survival of T1N0M0 stage human epidermal growth factor receptor 2 positive breast cancer: a real-world study / 中华肿瘤杂志

Objective: To investigate the prognosis impact of adjuvant trastuzumab treatment on human epidermal growth factor receptor 2 (HER-2) positive early breast cancer patients. Methods: A retrospective study was conducted, HER-2-positive T1N0M0 stage breast cancer patients who underwent surgery in the Affiliated Tumor Hospital of Xinjiang Medical University from January 2010 to December 2019 were divided into treatment group and control group according to whether they were treated with trastuzumab or not. Propensity score matching (PSM) was used to balance the confounding bias caused by differences in baseline characteristics between the two groups. Cox proportional hazards model was used to analyze the risk factors affecting disease-free survival (DFS). The Kaplan-Meier method was used to estimate the 3- and 5-year DFS and overall survival (OS) rates of the two groups before and after PSM. Results: There were 291 patients with HER-2 positive T1N0M0 stage breast cancer, including 21 cases in T1a (7.2%), 61 cases in T1b (21.0%), and 209 cases in T1c (71.8%). Before PSM, there were 132 cases in the treatment group and 159 cases in the control group, the 5-year DFS rate was 88.5%, and the 5-year OS rate was 91.5%. After PSM, there were 103 cases in the treatment group and 103 cases in the control group, the 5-year DFS rate was 86.0%, and the 5-year OS rate was 88.5%. Before PSM, there were significant differences in tumor size, histological grade, vascular invasion, Ki-67 index, postoperative chemotherapy or not and radiotherapy between the treatment group and the control group (P<0.05). After PSM, there were no significant difference in clinicopathological features between the treatment group and the control group (P>0.05). Multivariate analysis showed that histological grade (HR=2.927, 95 CI: 1.476, 5.805; P=0.002), vascular invasion (HR=3.410, 95 CI: 1.170, 9.940; P=0.025), menstrual status (HR=3.692, 95 CI: 1.021, 13.344, P=0.046), and chemotherapy (HR=0.238, 95 CI: 0.079, 0.720; P=0.011) were independent factors affecting DFS. After PSM, the 5-year DFS rate of the treatment group was 89.2%, while that of the control group was 83.5%(P=0.237). The 5-year OS rate of the treatment group was 96.1%, while that of the control group was 84.7%(P=0.036). Conclusion: Postoperative targeted therapy with trastuzumab can reduce the risk of recurrence and metastasis in patients with HER-2-positive T1N0M0 stage breast cancer.

Expert consensus on icotinib as adjuvant therapy for non-small cell lung cancer / 中华肿瘤杂志

Clinical studies have established the clinical application of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) adjuvant targeted therapy. Compared with chemotherapy, the high efficiency and low toxicity of targeted therapy increases the survival benefit of patients. Icotinib was the first EGFR-TKI with independent intellectual property rights in China and the third EGFR-TKI to be marketed in the world. In order to summarize the experience of icotinib and other EGFR-TKIs in the adjuvant treatment of non-small cell lung cancer and further standardize and guide the clinical application of icotinib, experts from the China International Exchange and Promotive Association for Medical and Health Care and the Guangdong Association of Thoracic Diseases have organized an expert consensus on the adjuvant treatment of non-small cell lung cancer with icotinib, which is expected to provide clinicians with evidence-based medical evidences for postoperative targeted drug using.

A small-molecule pan-HER inhibitor alone or in combination with cisplatin exerts efficacy against nasopharyngeal carcinoma / 医学前沿

The abnormal activation of HER family kinase activity is closely related to the development of human malignancies. In this study, we used HER kinases as targets for the treatment of nasopharyngeal carcinoma (NPC) and explored the anti-tumor effects of the novel pan-HER inhibitor HM781-36B, alone or in combination with cisplatin. We found that HER family proteins were positively expressed in tumor tissues of some NPC patients, and the high levels of those proteins were significantly related to poor prognosis. HM781-36B inhibited NPC in vitro and in vivo. HM781-36B exerted synergistic effects with cisplatin on inhibiting proliferation and promoting apoptosis of NPC cells. In NPC xenograft models in nude mice, HM781-36B and cisplatin synergistically inhibited tumor growth. Downregulating the activity of HER family proteins and their downstream signaling pathways and regulating tumor microenvironment may explain the synergistic anti-tumor effects of HM781-36B and cisplatin. In conclusion, our study provides evidence for HER family proteins as prognostic biomarkers and potential therapeutic targets for NPC. The pan-HER inhibitor HM781-36B alone or in combination with cisplatin represents promising therapeutic effects for the treatment of NPC patients, which provides a new idea for the comprehensive treatment of NPC.

CUDC-101 as a dual-target inhibitor of EGFR and HDAC enhances the anti-myeloma effects of bortezomib by regulating G2/M cell cycle arrest / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

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.

Research Progress in Immune Checkpoint Inhibitors Combination Therapy Applied to Non-small Cell Lung Cancer after EGFR Mutation-targeted Therapy Resistance / 中国肺癌杂志

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.

Chinese Expert Consensus on Non-small Cell Lung Cancer with EGFR Exon 20 Insertion Mutations (2023 Edition) / 中国肺癌杂志

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.

Advances in Diagnosis and Treatment of HER2-positive Non-small Cell Lung Cancer / 中国肺癌杂志

Lung cancer is the most common malignancy in the world and the leading cause of cancer death. Human epidermal growth factor receptor 2 (HER2) positive non-small cell lung cancer (NSCLC) refers to the NSCLC caused by mutation, amplification or overexpression of the HER2 gene, resulting in its dysfunction. HER2 is the most active receptor in the HER family and can combine with other members to form dimers, which can activate multiple signaling pathways and regulate cell proliferation, differentiation, migration and apoptosis. In NSCLC, HER2 positivity is usually considered a poor prognostic marker. At present, the diagnosis and treatment of HER2-positive NSCLC are not mature. Immunohistochemistry (IHC), next generation sequencing (NGS) and other technologies are often used to detect the positive status of HER2 mutation, amplification or overexpression. In previous studies, antitumor drugs did not show ideal therapeutic effects in HER2-positive NSCLC. However, in recent years, related researches have shown that antibody-drug conjugates (ADCs) and new tyrosine kinase inhibitors (TKIs) in targeted therapy show good antitumor activity against HER2 positive NSCLC. This article summarized the progress in diagnosis and treatment of HER2-positive NSCLC, so as to provide reference for subsequent researches.
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