• EGFR
• NSCLC
• TKI
• epidermal growth factor receptor protein tyrosine kinase
• non-small-cell lung cancer
• rechallenge
• retreatment
• tyrosine kinase inhibitors

• Humans
• Lung Neoplasms/drug therapy
• Lung Neoplasms/genetics
• Carcinoma, Non-Small-Cell Lung/drug therapy
• Carcinoma, Non-Small-Cell Lung/genetics
• Prospective Studies
• Protein Kinase Inhibitors/pharmacology
• Protein Kinase Inhibitors/therapeutic use
• Mutation
• Neoplasm Recurrence, Local/drug therapy
• Aniline Compounds/pharmacology
• Aniline Compounds/therapeutic use
• Treatment Outcome
• ErbB Receptors

Lung cancers are life-threatening malignancies that cause great healthcare burdens in Taiwan and worldwide. The 5-year survival rate for Taiwanese patients with lung cancer is approximately 29%, an unsatisfactorily low number that remains to be improved. We first reviewed the molecular epidemiology derived from a deep proteogenomic resource in Taiwan. The nuclear factor erythroid 2-related factor 2 (NRF2)antioxidant mechanism was discovered to mediate the oncogenesis and tumor progression of lung adenocarcinoma. Additionally, DNA replication, glycolysis and stress response are positively associated with tumor stages, while cell-to-cell communication, signaling, integrin, G protein coupled receptors, ion channels and adaptive immunity are negatively associated with tumor stages. Three patient subgroups were discovered based on the clustering analysis of protein abundance in tumors. The first subgroup is associated with more advanced cancer stages and visceral pleural invasion, as well as higher mutation burdens. The second subgroup is associated with EGFR L858R mutations. The third subgroup is associated with PI3K/AKT pathways and cell cycles. Both EGFR and PI3K/AKT signaling pathways have been shown to induce NRF2 activation and tumor cell proliferation. We also reviewed the clinical evidence of patient outcomes in Taiwan given various approved targeted therapies, such as EGFR-tyrosine kinase inhibitors and anaplastic lymphoma kinase (ALK)inhibitors, in accordance with the patients’ characteristics. Somatic mutations occurred in EGFR, KRAS, HER2 and BRAF genes, and these mutations have been detected in 55.7%, 5.2%, 2.0% and 0.7% patients, respectively. The EGFR mutation is the most prevalent targetable mutation in Taiwan. EML4-ALK translocations have been found in 9.8% of patients with wild-type EGFR. The molecular profiling of advanced NSCLC is critical to optimal therapeutic decision-making. The patient characteristics, such as mutation profiles, protein expression profiles, drug-resistance profiles, molecular oncogenic mechanisms and patient subgroup systems together offer new strategies for personalized treatments and patient care.

• ErbB Receptors/metabolism
• Humans
• Lung Neoplasms/pathology
• Mutation
• NF-E2-Related Factor 2/genetics
• Phosphatidylinositol 3-Kinases/genetics
• Protein Kinase Inhibitors/pharmacology
• Proto-Oncogene Proteins c-akt/genetics
• Taiwan/epidemiology

Background and Objectives: Epidermal growth factor receptor–tyrosine kinase inhibitors (EGFR-TKIs) are effective first-line chemotherapeutic agents for patients with advanced non-small-cell lung cancer (NSCLC) harboring drug-sensitive EGFR mutations. However, the effectiveness of EGFR-TKI rechallenge after first-line EGFR-TKI treatment is not sufficient in elderly patients (over 75 years of age) harboring drug-sensitive EGFR mutations. Therefore, we investigated the effectiveness and safety of EGFR-TKI rechallenge after first-line EGFR-TKI treatment in elderly patients with advanced NSCLC harboring drug-sensitive EGFR mutations. Materials and Methods: Between April 2008 and December 2015, we analyzed 78 elderly patients with advanced NSCLC harboring drug-sensitive EGFR mutations with first-line EGFR-TKI treatment at four Japanese institutions. We retrospectively evaluated the clinical effectiveness and safety profiles of EGFR-TKI rechallenge after first-line EGFR-TKI treatment in elderly patients with advanced NSCLC harboring drug-sensitive EGFR mutations (exon 19 deletion/exon 21 L858R mutation). Results: Twenty-two patients in the cohort were rechallenged with EGFR-TKI. The median age was 79.5 years (range 75–87 years). Despite the fact that it was a retrospective analysis, even with EGFR-TKI rechallenge treatment the response rate was 23%, progression-free survival was 5.3 months, and overall survival was 14.4 months. Common adverse events included rash acneiform, paronychia, diarrhea, and anorexia. There were no treatment-related deaths. Due to the occurrence of adverse events of grade 2 or more, dose reduction was performed in 15 (68.2%) of 22 cases. Conclusions: EGFR-TKI rechallenge treatment after first-line EGFR-TKI treatment in elderly patients with advanced NSCLC harboring drug-sensitive EGFR mutations was one of the limited, safe and effective treatment options for elderly EGFR-positive lung cancer patients.

• EGFR mutations
• EGFR-TKI
• advanced non-small-cell lung cancer
• elderly patients
• epidermal growth factor receptor
• re-administration
• secondary chemotherapy
• tyrosine kinase inhibitor

Osimertinib is the recommended first-line treatment for adult patients with epidermal growth factor receptor (EGFR) mutation positive advanced or metastatic non-small cell lung cancer (NSCLC). However, primary or acquired resistance to EGFR-tyrosine kinase inhibitors (EGFR-TKIs) seems inevitable, and when drug-resistance occurs during treatment with osimertinib, the standard of care is to discontinue the TKI.

A 57-year-old female patient with lung adenocarcinoma presented with an irritating cough accompanied by chest distress of one month duration. An enhanced head magnetic resonance imaging scan showed brain metastases. An EGFR mutation (exon 21 L858R) was detected in pleural fluid. The patient was treated with oral osimertinib (80 mg once daily) from January 2018 but developed progressive disease on December 2018. She was then successfully treated with re-challenge and tri-challenge with osimertinib (80 mg once daily) by resensitization chemotherapy twice after the occurrence of drug-resistance to osimertinib, and to date has survived for 31 mo.

This case may provide some selective therapeutic options for NSCLC patients with acquired drug-resistance who were previously controlled on osimertinib treatment.

• Osimertinib
• Retreatment
• Epidermal growth factor receptor
• Tyrosine kinase inhibitor
• Non-small cell lung cancer
• Case report

Many studies have reported that estrogen (E2) promotes lung cancer by binding to nuclear estrogen receptors (ER), and altering ER related nuclear protein expressions. With the GEO database analysis, Human centromere protein F (CENPF) is highly expressed in lung adenocarcinoma (LUAD), and the co-expression of CENPF and ERβ was found in the nucleus of LUAD cells through immunofluorescence. We identified the nuclear protein CENPF and explored its relationship with the ER pathway. CENPF and ERβ2/5 were related with T stage and poor prognosis (P<0.05). CENPF knockout significantly inhibited LUAD cell growth, the tumor growth of mice and the expression of ERβ2/5 (P<0.05). The protein expression of CENPF and ERβ2/5 in the CENPF-Knockdown+Fulvestrant group was lower than CENPF- Negative Control +Fulvestrant group (P=0.002, 0.004, 0.001) in A549 cells. The tumor size and weight of the CENPF-Knockdown+Fulvestrant group were significantly lower than CENPF- Negative Control +Fulvestrant group (P=0.001, 0.039) in nude mice. All the results indicated that both CENPF and ERβ2/5 play important roles in the progression of LUAD, and knockdown CENPF can inhibit the progression of LUAD by inhibiting the expression of ER2/5. Thus, the development of inhibitors against ERβ2/5 and CENPF remained more effective in improving the therapeutic effect of LUAD.

• WGCNA package
• centromere protein F (CENPF)
• estrogen receptor beta
• lung adenocarcinoma (LUAD)
• non-small cell lung cancer (NSCLC)

• Algorithm
• Chronobiology
• Drug resistance
• Tumor resistance

• Antineoplastic Agents/pharmacology
• Antineoplastic Agents/therapeutic use
• Drug Resistance, Neoplasm/drug effects
• Humans
• Neoplasms/drug therapy
• Neoplasms/pathology

• Amplification refractory mutation system (ARMS)
• Droplet digital PCR (ddPCR)
• Epidermal growth factor receptor (EGFR)
• Mutation abundance
• Non-small-cell lung cancer (NSCLC)
• Tyrosine kinase inhibitor (TKI)

• Antineoplastic Agents/therapeutic use
• Biological Products/therapeutic use
• Clinical Trials as Topic
• Drug Development
• Drug Therapy, Combination
• Forecasting
• Humans
• Molecular Targeted Therapy/methods
• Molecular Targeted Therapy/trends
• Neoplasms/drug therapy
• Precision Medicine/methods
• Precision Medicine/trends
• Protein Kinase Inhibitors/therapeutic use

Objective: Explore the mechanism of CaSR's involvement in bone metastasis in lung adenocarcinoma.

Methods: Immunohistochemistry (IHC) was used to detect the expression of calcium-sensing receptor (CaSR) in 120 cases of lung adenocarcinoma with bone metastasis. Stably transfected cell lines with CaSR overexpression and knockdown based on A549 cells were constructed. The expression of CaSR was verified by western blot and qPCR. The proliferation and migration abilities of A549 cells were tested using cholecystokinin-8 (CCK-8) and Transwell assays, respectively. Western blotting was used to detect the expression of matrix metalloproteinases MMP2, MMP9, CaSR, and NF-κB. The supernatant from each cell culture group was collected as a conditional co-culture solution to study the induction of osteoclast precursor cells and osteoblasts. Western blot and qPCR were used to validate the expression of bone matrix degradation-related enzymes cathepsin K and hormone calcitonin receptor (CTR) and osteoblast-induced osteoclast maturation and differentiation enzyme receptor activator of nuclear factor-κB ligand (RANKL), macrophage colony-stimulating factor (M-CSF), osteoprotegerin (OPG), and PTHrP. Immunofluorescent staining was used to detect F-actin ring formation and osteocalcin expression. Western blot results for NF-κB expression identified a regulatory relationship between NF-κB and CaSR.

Results: CaSR expression in lung cancer tissues was significantly higher than that in adjacent and normal lung tissues. The expression of CaSR in lung cancer tissues with bone metastasis was higher than that in non-metastatic lung cancer tissues. The proliferation and migration ability of A549 cells increased significantly with overexpressed CaSR. The co-culture solution directly induced osteoclast precursor cells and the expression of bone matrix degradation-related enzymes significantly increased. Osteoblasts were significantly inhibited and osteoblast-induced osteoclast maturation and differentiation enzymes were significantly downregulated. It was found that the expression of NF-κB and PTHrP increased when CaSR was overexpressed. Osteoclast differentiation factor expression was also significantly increased, which directly induces osteoclast differentiation and maturation. These results were reversed when CaSR was knocked down.

Conclusions: CaSR can positively regulate NF-κB and PTHrP expression in A549 cells with a high metastatic potential, thereby promoting osteoclast differentiation and maturation, and facilitating the occurrence and development of bone metastasis in lung adenocarcinoma.

• bone metastasis
• calcium-sensing receptor
• lung adenocarcinoma
• migration
• proliferation

• Afatinib
• Epidermal growth factor receptor mutation
• Frist line
• Non-small cell lung cancer
• Re-challenge

It is less known about miRNA3127‐5p induced up‐regulation of PD‐L1, immune escape and drug resistance caused by increased PD‐L1 in lung cancer. In this study, lentivirus was transduced into lung cancer cells, and quantitative PCR and Western blot were used to detect the expression of PD‐L1. Then immunofluorescence assay was applied to detect autophagy, finally we explored the relationship between PD‐L1 expressions and chemoresistance in patients. As a result, we found that microRNA‐3127‐5p promotes pSTAT3 to induce the expression of PD‐L1; microRNA‐3127‐5p promotes STAT3 phosphorylation through suppressing autophagy, and autophagy could retaine pSTAT3 into the nucleus in miRNA‐3127‐5p knocked cells, and immune escape induced by elevated level of PD‐L1 results in chemoresistance of lung cancer. In conclusion, microRNA‐3127‐5p induces PD‐L1 elevation through regulating pSTAT3 expression. We also demonstrate that immune escape induced by PD‐L1 can be dismissed by corresponding monoclonal antibody.

• JAK/STAT3
• PD-L1
• immune escape
• lung cancer
• microRNA-3127-5p

• Afatinib
• Compassionate use pragram
• Epidermal growth factor receptor
• Non-small cell lung cancer

Epidermal growth factor receptor (EGFR) T790M mutation serves as an important predictor of osimertinib efficacy. However, little is known about how it works among patients with various timings of T790M emergence and treatment.

Advanced EGFR-mutant lung adenocarcinoma patients with positive T790M mutation in tumor were retrospectively enrolled and observed to determine the outcomes of osimertinib treatment. We evaluated the association between patients’ characteristics and the efficacy of osimertinib treatment, particularly with respect to the timing of T790M emergence and osimertinib prescription.

A total of 91 patients were enrolled, including 14 (15.4%) with primary and 77 (84.6%) with acquired T790M mutation. The objective response rate and disease controlratewere 60.9% and 85.1%, respectively. The median progression-free survival (PFS) and overall survival were 11.5 months (95% confidence interval [CI], 9.0 to 14.0) and 30.4 months (95% CI, 11.3 to 49.5), respectively. There was no significant difference in response rate and PFS between primary and acquired T790M populations. In the acquired T790M subgroup, patientswho received osimertinib after T790M had been confirmed by rebiopsy had a longer PFS than those with intercalated treatments between rebiopsy and osimertinib prescription (14.0 months [95% CI, 9.0 to 18.9] vs. 7.2 months [95% CI, 3.7 to 10.8]; adjusted hazard ratio, 0.48 [95% CI, 0.24 to 0.98; p=0.043]). Rebiopsy timing did not influence the outcome.

Osimertinib prescription with intercalated treatment following rebiopsy but not the timing of T790M emergence influenced the treatment outcome. We suggest that it is better to start osimertinib treatment once T790M mutation has been confirmed by biopsy.

• Epidermal growth factor receptor
• Lung adenocarcinoma
• Osimertinib

Tyrosine kinase inhibitors (TKIs) are currently the first-line treatment for non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations. These patients receive platinum-based chemotherapy as the second-line treatment after they develop resistance to TKIs. Many patients regain sensitivity to the TKIs used in the first-line treatment after the failure of chemotherapy. However, the molecular mechanism for the regain of TKI sensitivity is largely unknown. In this study, we established gefitinib-resistant PC9 and HCC827 cell lines, which did not harbor the EGFR T790M mutation and MET amplification but exhibited the epithelial-mesenchymal transition (EMT) phenotype. Overexpression of EMT inducers, Snail or Slug, in the parental lines promoted their resistance to gefitinib. The gefitinib-resistant cell lines regained their sensitivity to gefitinib and displayed reverse EMT phenotypes after long-term culture in gefitinib-free culture medium. Blockage of reverse EMT by stable expression of Snail or Slug prevented the regain of TKI sensitivity. In conclusion, reverse EMT is one of the major mechanisms for the regain of TKI sensitivity in TKI-resistant NSCLC cells, suggesting that the development of small molecules targeting the EMT process may prolong the efficacy of TKIs in NSCLC patients with EGFR mutations.

• Antineoplastic Agents/pharmacology
• Cell Line, Tumor
• Cell Proliferation/drug effects
• Drug Resistance, Neoplasm/drug effects
• Drug Resistance, Neoplasm/genetics
• Epithelial Cells/drug effects
• Epithelial Cells/metabolism
• Epithelial Cells/pathology
• Epithelial-Mesenchymal Transition/drug effects
• Epithelial-Mesenchymal Transition/genetics
• ErbB Receptors/genetics
• ErbB Receptors/metabolism
• Gefitinib
• Gene Expression Regulation, Neoplastic
• Humans
• Mutation
• Protein Kinase Inhibitors/pharmacology
• Quinazolines/pharmacology
• Signal Transduction
• Snail Family Transcription Factors/genetics
• Snail Family Transcription Factors/metabolism

• Ministry of Science and Technology, Taiwan
• Kaohsiung Medical University (TW)
• Kaohsiung Municipal Ta-Tung Hospital
• Kaohsiung Medical University
• Kaohsiung Medical University Hospital

Although EGFR-TKIs (epidermal growth factor receptor tyrosine kinase inhibitors) induce favorable responses as first-line non-small cell lung cancer treatments, drug resistance remains a serious problem. Meanwhile, thermal therapy also shows promise as a cancer therapy strategy. Here we combine a novel EGFR-TKI treatment with thermal therapy to improve lung cancer treatment outcomes.

The results suggest that the cAMP-H₃BO₃ complex effectively inhibits EGFR auto-phosphorylation, while inducing apoptosis and cell cycle arrest in vitro. Compared to the negative control, tumor growth was significantly suppressed in mice treated with oxidative phosphorylation uncoupler thyroxine sodium and either cAMP-H₃BO₃ complex or cAMP-H₃BO₃ complex (P < 0.05). Moreover, the body temperature increase induced by treatment with thyroxine sodium inhibited tumor growth. Immunohistochemical analyses showed that A549 cell apoptosis was significantly higher in the cAMP-H₃BO₃ complex plus thyroxine sodium treatment group than in the other groups. Moreover,Ca²⁺ content analysis showed that the Ca²⁺ content of tumor tissue was significantly higher in the cAMP-H₃BO₃ complex plus thyroxine sodium treatment group than in other groups.

Inhibition of EGFR auto-phosphorylation by cAMP and cAMP-H₃BO₃ complex was studied using autoradiography and western blot. The antitumor activity of the novel EGFR inhibitor (cAMP-H₃BO₃ complex) with or without an oxidative phosphorylation uncoupler (thyroxine sodium) was investigated in vitro and in a nude mouse xenograft lung cancer model incorporating human A549 cells.

cAMP-H₃BO₃ complex is a novel EGFR-TKI. Combination therapy using cAMP-H₃BO₃ with thyroxine sodium-induced thermal therapy may improve lung cancer treatment outcomes.

• EGFR-TKI
• NSCLC
• cAMP-H3BO3 complex
• thermal therapy

• Clonality
• Liquid biopsy
• Lung cancer
• Mutation rate
• Non-invasive

• Adult
• Aged
• Aged, 80 and over
• Antineoplastic Agents/therapeutic use
• Chemoradiotherapy
• Clone Cells
• DNA, Neoplasm/genetics
• Disease Progression
• ErbB Receptors/antagonists & inhibitors
• Erlotinib Hydrochloride/therapeutic use
• Female
• Gene Expression Profiling
• Genes, Neoplasm
• Genes, erbB-1
• Genes, p53
• Genes, ras
• Humans
• Lung Neoplasms/genetics
• Lung Neoplasms/mortality
• Lung Neoplasms/therapy
• Male
• Middle Aged
• Mutation
• Neoplasm Invasiveness/genetics
• Neoplasm Proteins/genetics
• Neoplasms/genetics
• Neoplasms/mortality
• Neoplasms/pathology
• Neoplastic Cells, Circulating
• Neoplastic Stem Cells
• Protein Kinase Inhibitors/therapeutic use
• Retrospective Studies
• Sequence Analysis, DNA
• Smoking/genetics

• P30 CA012197 NCI NIH HHS
• National Cancer Institute