The third-generation epidermal growth factor receptor (EGFR) inhibitor osimertinib (OSI) has been approved as the first-line treatment for EGFR-mutant non-small cell lung cancer (NSCLC). This study aims to explore a rational combination strategy for enhancing the OSI efficacy. In this study, OSI induced higher CD47 expression, an important anti-phagocytic immune checkpoint, via the NF-κB pathway in EGFR-mutant NSCLC HCC827 and NCI-H1975 cells. The combination treatment of OSI and the anti-CD47 antibody exhibited dramatically increasing phagocytosis in HCC827 and NCI-H1975 cells, which highly relied on the antibody-dependent cellular phagocytosis effect. Consistently, the enhanced phagocytosis index from combination treatment was reversed in CD47 knockout HCC827 cells. Meanwhile, combining the anti-CD47 antibody significantly augmented the anticancer effect of OSI in HCC827 xenograft mice model. Notably, OSI induced the surface exposure of "eat me" signal calreticulin and reduced the expression of immune-inhibitory receptor PD-L1 in cancer cells, which might contribute to the increased phagocytosis on cancer cells pretreated with OSI. In summary, these findings suggest the multidimensional regulation by OSI and encourage the further exploration of combining anti-CD47 antibody with OSI as a new strategy to enhance the anticancer efficacy in EGFR-mutant NSCLC with CD47 activation induced by OSI.
Humans ; Mice ; Animals ; Carcinoma, Non-Small-Cell Lung/metabolism* ; Lung Neoplasms/metabolism* ; Acrylamides/pharmacology* ; ErbB Receptors/metabolism* ; Cell Line, Tumor ; CD47 Antigen/therapeutic use*

Abivertinib, a third-generation tyrosine kinase inhibitor, is originally designed to target epidermal growth factor receptor (EGFR)-activating mutations. Previous studies have shown that abivertinib has promising antitumor activity and a well-tolerated safety profile in patients with non-small-cell lung cancer. However, abivertinib also exhibited high inhibitory activity against Bruton's tyrosine kinase and Janus kinase 3. Given that these kinases play some roles in the progression of megakaryopoiesis, we speculate that abivertinib can affect megakaryocyte (MK) differentiation and platelet biogenesis. We treated cord blood CD34⁺ hematopoietic stem cells, Meg-01 cells, and C57BL/6 mice with abivertinib and observed megakaryopoiesis to determine the biological effect of abivertinib on MK differentiation and platelet biogenesis. Our in vitro results showed that abivertinib impaired the CFU-MK formation, proliferation of CD34⁺ HSC-derived MK progenitor cells, and differentiation and functions of MKs and inhibited Meg-01-derived MK differentiation. These results suggested that megakaryopoiesis was inhibited by abivertinib. We also demonstrated in vivo that abivertinib decreased the number of MKs in bone marrow and platelet counts in mice, which suggested that thrombopoiesis was also inhibited. Thus, these preclinical data collectively suggested that abivertinib could inhibit MK differentiation and platelet biogenesis and might be an agent for thrombocythemia.
Acrylamides/pharmacology* ; Animals ; Blood Platelets/drug effects* ; Cell Differentiation ; Megakaryocytes/drug effects* ; Mice ; Mice, Inbred C57BL ; Piperazines/pharmacology* ; Pyrimidines/pharmacology*

Lung cancer is the sixth leading cause of death worldwide and one of the leading cause of death from malignant tumors. Non-small cell lung cancer (NSCLC) is the most common type of lung cancer. Epidermal growth factor receptor (EGFR) gene mutation is a common mutation in NSCLC. For advanced NSCLC patients with EGFR mutations, EGFR-tyrosine kinase inhibitors (EGFR-TKIs), such as Gefitinib, Afatinib, Oxitinib and other targeted therapies have become the first-line treatment recommended by many guidelines, but many patients develop acquired drug resistance after about 1 year of medication. Patients with drug resistance will have earlier disease progression than patients without drug resistance, which has an important impact on the prognosis of patients. At present, the main treatment for patients with acquired resistance is new target inhibition for resistant mutation. For example, if patients with T790M mutation are resistant to the first or second generation drugs such as Gefitinb and Afatinib, they can be treated with the third generation drugs (Osimertinib or Almonertinib), which can delay the progression of the disease. Therefore, the study of drug resistance mechanism and treatment of drug resistance patients are essential. This paper mainly reviews targeted therapy and drug resistance mechanism of EGFR-mutant NSCLC patients, in order to provide reference for clinical application of EGFR-TKIs.
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Acrylamides ; Carcinoma, Non-Small-Cell Lung/pathology* ; Drug Resistance, Neoplasm/genetics* ; ErbB Receptors/genetics* ; Genes, erbB-1 ; Humans ; Indoles ; Lung Neoplasms/pathology* ; Mutation ; Protein Kinase Inhibitors/therapeutic use* ; Pyrimidines

OBJECTIVE: To investigate the effects of AZD9291 on the proliferation and migration of nasopharyngeal carcinoma cells. METHODS: Nasopharyngeal carcinoma HNE1 and CNE2Z cells were treated with AZD9291 at the doses of 0.5, 1, 2, 4, and 8 μmol/L and at the doses of 1, 2, 4, 8, and 16 μmol/L, respectively. Cell survival was measured using CCK8 assay, and proliferation inhibition of the cells after AZD9291 treatment was examined with colony-forming assay; the cell repair and migration abilities were determined using scratch assay and Transwell experiment. The expressions of EGFR-related signaling proteins and migration-related proteins were detected using Western blotting. RESULTS: The results of CCK8 assay and colonyforming assay showed that AZD9291 significantly inhibited the viability and proliferation of both HNE1 and CNE2Z cells (P < 0.01). AZD9291 treatment also attenuated the migration ability of HNE1 and CNE2Z cells (P < 0.01). Western blotting showed that, as the concentration of AZD9291 increased, the expression levels of the proteins involved in the PI3K-AKT-mTOR signaling pathway were lowered progressively (P < 0.01), resulting in inhibition of migration of HNE1 and CNE2Z cells (P < 0.01). CONCLUSION AZD9291 suppresses proliferation and attenuates repair and migration capacities of nasopharyngeal carcinoma cells by inhibiting the EGFR/PI3K/AKT/mTOR signaling pathway, suggesting the potential value of AZD9291 in the treatment of nasopharyngeal carcinoma.
Acrylamides ; Aniline Compounds ; Cell Line, Tumor ; Cell Movement ; Cell Proliferation ; ErbB Receptors ; Humans ; Indoles ; Nasopharyngeal Carcinoma/pathology* ; Nasopharyngeal Neoplasms/pathology* ; Phosphatidylinositol 3-Kinases/metabolism* ; Proto-Oncogene Proteins c-akt/metabolism* ; Pyrimidines ; TOR Serine-Threonine Kinases/metabolism*

Osimertinib-induced interstitial lung disease (ILD) is an uncommon, but fatal pulmonary toxicity in some patients. We report a case of a 64-year-old male with stage IV adeno-non-small cell lung cancer (NSCLC) harboring an exon 19 deletion in the epidermal growth factor receptor (EGFR) treated with osimertinib 80 mg/d for first-line targeted therapy. On day 60 after initiating treatment of osimertinib, the patient developed ILD. Osimertinib was discontinued immediately and oral prednisone 60 mg/d was initiated, ILD improved within 13 d. After balancing the risk and benefit, osimertinib was restarted concurrently with prednisone. The patient showed neither disease progression nor a recurrence of ILD for more than 16 months. Based on our case and literature review, retreatment with osimertinib under steroid coverage could be considered as an effective treatment option after careful risk-benefit assessment for patients with EGFR-mutant NSCLC.
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Acrylamides/therapeutic use* ; Aniline Compounds/therapeutic use* ; Carcinoma, Non-Small-Cell Lung/genetics* ; ErbB Receptors/genetics* ; Humans ; Lung Diseases, Interstitial/genetics* ; Lung Neoplasms/genetics* ; Male ; Middle Aged ; Prednisone ; Protein Kinase Inhibitors/adverse effects*

OBJECTIVES: Lung cancer is one of the most common malignant tumors in the world, and its lethality ranks the first among many malignant tumors. For non-small cell lung cancer (NSCLC) patients, due to the high mortality rate, the overall 5-year survival rate is less than 15%. When NSCLC undergoes local invasion, the 5-year survival rate is only 20%, and it is even lower when distant metastasis occurs up to 4%. Almonertinib is an innovative drug independently researched and developed by China with independent intellectual property rights. As an epidermal growth factor receptor tyrosine kinase inhibitor, almonertinib is mainly used for locally advanced or metastatic NSCLC patients with epidermal growth factor receptor (EGFR) T790M mutation. This study aims to investigate the effects of almonertinib on the proliferation, invasion and migration of NSCLC cells in vitro. METHODS: NSCLC cells H1975 and PC-9 were cultured in vitro. The effects of almonertinib on the proliferation, apoptosis, invasion, and migration of H1975 and PC-9 cells were detected by CCK-8 assay, apoptotic assay and Transwell assay. The expression of invasion and migration related proteins was detected by Western blotting. RESULTS: The CCK-8 experiment showed that almonertinib inhibited the proliferation of H1975 and PC-9 cells in a time- and dose-dependent manner. The IC CONCLUSIONS Almonertinib can inhibit the proliferation, invasion, and migration of NSCLCH1975 and PC-9 cells in vitro and vivo, and promote the apoptosis of H1975 and PC-9 cells. The underlying mechanism may be related to the inhibition of tumor cell epithelial mesenchymal transformation and metalloproteinase expression.
Acrylamides ; Animals ; Apoptosis ; Carcinoma, Non-Small-Cell Lung/drug therapy* ; Cell Line, Tumor ; Cell Proliferation ; Drug Resistance, Neoplasm ; ErbB Receptors/genetics* ; Humans ; Indoles ; Lung Neoplasms ; Mice ; Mice, Nude ; Mutation ; Protein Kinase Inhibitors/pharmacology* ; Pyrimidines

OBJECTIVE: Pyrotinib, a novel irreversible pan-ErbB receptor tyrosine kinase inhibitor, showed promising antitumor activity and acceptable tolerability in phase II and phase III randomized clinical trials. We assessed the activity and safety of oral pyrotinib for human epidermal growth factor receptor 2 (HER2) positive metastatic breast cancer patients in the real world. METHODS: We retrospectively analyzed 72 HER2 positive metastatic breast cancer (MBC) patients who received oral pyrotinib based regimens at Beijing Cancer Hospital and other four hospitals (Peking University First Hospital, China-Japan Friendship Hospital, General Hospital of PLA, Peking University Third Hospital) from August 2018 to September 2019. Progression free survival (PFS), objective response rate (ORR), adverse events (AE) of pyrotinib were investigated. RESULTS: Seventy-two patients with HER2 positive MBC were enrolled. The median age of the patients was 55 years (range: 32-79 years). Sixty-nine (95.8%) patients had received anti-HER2 treatment in the metastatic and/or (neo) adjuvant settings; 61 (84.7%) patients had received anti-HER2 treatments in the metastatic setting in terms of trastuzumab 56 (77.8%) patients, lapatinib 36 (50.0%) patients, and T-DM1 4 (5.6%) patients. Among these 72 patients who received oral pyrotinib based regimens, 62 (86.1%) patients received pyrotinib (±trastuzumab) in combination with chemotherapy, 6 (8.3%) patients received pyrotinib (± trastuzumab) in combination with endocrine therapy and 4 (5.6%) patients received pyrotinib (±trastuzumab). Sixty-five (90.3%) patients received 400 mg pyrotinib once daily as initial dose, and 7 (9.7%) patients received 320 mg. OBJECTIVE response and safety to pyrotinib based therapy were evaluable in all the 72 patients. One (1.4%) patient achieved complete response (CR), 18 (25.0%) patients achieved partial response (PR), 41 (56.9%) patients had stable disease (SD), and 12 (16.7%) patients had progressive disease (PD). The ORR (CR+PR) was 26.4% and the median PFS was 7.6 months (95%CI: 5.5-9.7 months). Among the 36 patients with prior lapatinib therapy, the median PFS was 7.9 months (95%CI: 4.1-11.7 months). Among the 15 patients with brain metastasis, the median PFS was 6.0 months (95%CI: 2.2-9.8 months). The main toxicities related to pyrotinib were diarrhea in 57 (79.2%) cases, and 48 (66.7%) cases with grade 1-2 as well as 9 (12.5%) cases with grade 3. CONCLUSION Pyrotinib based therapy is an effective treatment for patients with HER2 positive MBC, including patients with lapatinib treatment failure and brain metastasis, and the toxicities can be tolerated.
Acrylamides/therapeutic use* ; Adult ; Aged ; Aminoquinolines/therapeutic use* ; Antineoplastic Combined Chemotherapy Protocols ; Breast Neoplasms/drug therapy* ; China ; Humans ; Middle Aged ; Neoplasm Metastasis ; Receptor, ErbB-2 ; Retrospective Studies ; Trastuzumab ; Treatment Outcome

Acrylamides ; Aniline Compounds ; Carcinoma, Non-Small-Cell Lung/genetics* ; Crizotinib/therapeutic use* ; Drug Resistance, Neoplasm/genetics* ; Erlotinib Hydrochloride/therapeutic use* ; Humans ; Lung Neoplasms/genetics* ; Mutation ; Protein Kinase Inhibitors/therapeutic use* ; Proto-Oncogene Proteins c-met/genetics*

Oxidative stress and apoptosis are the key factors that limit the hypothermic preservation time of donor hearts to within 4-6 h. The aim of this study was to investigate whether the histone deacetylase 3 (HDAC3) inhibitor RGFP966 could protect against cardiac injury induced by prolonged hypothermic preservation. Rat hearts were hypothermically preserved in Celsior solution with or without RGFP966 for 12 h followed by 60 min of reperfusion. Hemodynamic parameters during reperfusion were evaluated. The expression and phosphorylation levels of mammalian STE20-like kinase-1 (Mst1) and Yes-associated protein (YAP) were determined by western blotting. Cell apoptosis was measured by the terminal deoxynucleotidyl-transferase (TdT)-mediated dUTP nick-end labeling (TUNEL) method. Addition of RGFP966 in Celsior solution significantly inhibited cardiac dysfunction induced by hypothermic preservation. RGFP966 inhibited the hypothermic preservation-induced increase of the phosphorylated (p)-Mst1/Mst1 and p-YAP/YAP ratios, prevented a reduction in total YAP protein expression, and increased the nuclear YAP protein level. Verteporfin (VP), a small molecular inhibitor of YAP-transcriptional enhanced associate domain (TEAD) interaction, partially abolished the protective effect of RGFP966 on cardiac function, and reduced lactate dehydrogenase activity and malondialdehyde content. RGFP966 increased superoxide dismutase, catalase, and glutathione peroxidase gene and protein expression, which was abolished by VP. RGFP966 inhibited hypothermic preservation-induced overexpression of B-cell lymphoma protein 2 (Bcl-2)-associated X (Bax) and cleaved caspase-3, increased Bcl-2 mRNA and protein expression, and reduced cardiomyocyte apoptosis. The antioxidant and anti-apoptotic effects of RGFP966 were cancelled by VP. The results suggest that supplementation of Celsior solution with RGFP966 attenuated prolonged hypothermic preservation-induced cardiac dysfunction. The mechanism may involve inhibition of oxidative stress and apoptosis via inactivation of the YAP pathway.
Acrylamides/pharmacology* ; Animals ; Apoptosis/drug effects* ; Cryopreservation ; Disaccharides/pharmacology* ; Electrolytes/pharmacology* ; Glutamates/pharmacology* ; Glutathione/pharmacology* ; Heart/physiology* ; Heart Transplantation/methods* ; Hepatocyte Growth Factor/antagonists & inhibitors* ; Histidine/pharmacology* ; Histone Deacetylase Inhibitors/pharmacology* ; Intracellular Signaling Peptides and Proteins/antagonists & inhibitors* ; Male ; Mannitol/pharmacology* ; Oxidative Stress/drug effects* ; Phenylenediamines/pharmacology* ; Proto-Oncogene Proteins/antagonists & inhibitors* ; Rats ; Rats, Sprague-Dawley ; Signal Transduction/drug effects* ; YAP-Signaling Proteins

Acrylamides ; therapeutic use ; Aged ; Aniline Compounds ; therapeutic use ; Carcinoma, Non-Small-Cell Lung ; drug therapy ; genetics ; Crown Ethers ; therapeutic use ; ErbB Receptors ; genetics ; metabolism ; Female ; Humans ; Lung Neoplasms ; drug therapy ; genetics ; Mutation ; genetics ; Quinazolines ; therapeutic use