• cancer therapeutic resistance
• targeted therapies
• non-small-cell lung cancer
• target identification

• Humans
• Neoplasms/drug therapy
• Patient Reported Outcome Measures
• Clinical Trials as Topic
• Adverse Drug Reaction Reporting Systems
• Drug-Related Side Effects and Adverse Reactions

• The University of Queensland

• Cardiac arrhythmia
• Cardiovascular adverse event
• Epidermal growth factor receptor
• Sudden cardiac death

• Humans
• Carcinoma, Non-Small-Cell Lung/drug therapy
• Carcinoma, Non-Small-Cell Lung/complications
• Heart Failure/drug therapy
• Lung Neoplasms/drug therapy
• Lung Neoplasms/complications
• ErbB Receptors/antagonists & inhibitors
• ErbB Receptors/genetics
• Torsades de Pointes/chemically induced
• Protein Kinase Inhibitors/therapeutic use
• Protein Kinase Inhibitors/adverse effects
• Long QT Syndrome/chemically induced
• Incidence
• Tyrosine Kinase Inhibitors

• EGFR inhibitor
• dacomitinib
• overall survival
• pharmacokinetics
• progression-free survival
• proton-pump inhibitors

• Dacomitinib
• Efficacy
• Non-small cell lung cancer
• Safety
• Uncommon EGFR mutation

• Humans
• Carcinoma, Non-Small-Cell Lung/drug therapy
• Carcinoma, Non-Small-Cell Lung/genetics
• Carcinoma, Non-Small-Cell Lung/pathology
• Lung Neoplasms/drug therapy
• Lung Neoplasms/genetics
• Lung Neoplasms/pathology
• Cohort Studies
• Antineoplastic Agents/therapeutic use
• Protein Kinase Inhibitors/adverse effects
• ErbB Receptors
• Mutation

• Y-2019Genecast-024 Heath Research Foundation of Chinese Society of Clinical Oncology
• 2021JJ30430 Hunan Provincial Natural Science Foundation of China
• 20201566 Project of Health and Health Commission of Hunan Province
• ZX2020005-5 and YF2020005 Hunan Cancer Hospital Climb Plan
• Y-XD202001-0215 Beijing Xisike Clinical Oncology Research Foundation
• 2023SK4024 the science and technology innovation Program of Hunan Province

• ALK
• Apoptosis
• Dual kinase inhibitor
• EGFR
• Non-small cell lung cancer

• Humans
• Carcinoma, Non-Small-Cell Lung/drug therapy
• Carcinoma, Non-Small-Cell Lung/genetics
• Carcinoma, Non-Small-Cell Lung/metabolism
• Lung Neoplasms/drug therapy
• Lung Neoplasms/genetics
• Lung Neoplasms/metabolism
• Ligands
• ErbB Receptors
• Phosphorylation
• Mutation
• Protein Kinase Inhibitors/pharmacology
• Protein Kinase Inhibitors/chemistry
• Cell Line, Tumor
• Oncogene Proteins, Fusion/genetics
• Oncogene Proteins, Fusion/metabolism

• Dacomitinib
• brain metastases
• lung cancer
• uncommon mutations

• ALK
• BCR-ABL
• BRAF
• BTK inhibitor
• EGFR
• FDA
• MEK
• cancer kinase inhibitors

New series of thiazolyl-pyrazoline derivatives (7a–7d, 10a–10d and 13a–13f) have been synthesised and assessed for their potential EGFR and VEGFR-2 inhibitory activities. Compounds 10b and 10d exerted potent and selective inhibitory activity towards the two receptor tyrosine kinases; EGFR (IC₅₀ = 40.7 ± 1.0 and 32.5 ± 2.2 nM, respectively) and VEGFR-2 (IC₅₀ = 78.4 ± 1.5 and 43.0 ± 2.4 nM, respectively). The best anti-proliferative activity for the examined thiazolyl-pyrazolines was observed against the non-small lung cancer cells (NSCLC). Compounds 10b and 10d displayed pronounced efficacy against A549 (IC₅₀ = 4.2 and 2.9 µM, respectively) and H441 cell lines (IC₅₀ = 4.8 and 3.8 µM, respectively). Moreover, our results indicated that 10b and 10d were much more effective towards EGFR-mutated NSCLC cell lines (NCI-H1650 and NCI-H1975 cells) than gefitinib. Finally, compounds 10b and 10d induce G2/M cell cycle arrest and apoptosis and inhibit migration in A549 cancerous cells.

• Anticancer
• EGFR inhibitors
• EGFR-mutated NSCLC
• VEGFR-2 inhibitors
• dual kinase inhibitors
• molecular docking

• afatinib
• dacomitinib
• efficacy
• non-small cell lung cancer
• progression patterns
• resistance
• safety
• uncommon EGFR mutations

• (Grant No. 2021-053-ZZ). Beijing Health Promotion Association

Non-small cell lung cancer (NSCLC) has one of the highest cancer-related mortality rates worldwide. In a subgroup of NSCLC, tumor growth is driven by epidermal growth factor receptors (EGFR) that harbor an activating mutation. These patients are best treated with EGFR tyrosine kinase inhibitors (EGFR TKI). Identifying the EGFR mutational status on a tumor biopsy or a liquid biopsy using tumor DNA sequencing techniques is the current approach to predict tumor response on EGFR TKI therapy. However, due to difficulty in reaching tumor sites, and varying inter- and intralesional tumor heterogeneity, biopsies are not always possible or representative of all tumor lesions, highlighting the need for alternative biomarkers that predict tumor response. Positron emission tomography (PET) studies using EGFR TKI-based tracers have shown that EGFR mutational status could be identified, and that tracer uptake could potentially be used as a biomarker for tumor response. However, despite their likely predictive and monitoring value, the EGFR TKI-PET biomarkers are not yet qualified to be used in the routine clinical practice. In this review, we will discuss the currently investigated EGFR-directed PET biomarkers, elaborate on the typical biomarker development process, and describe how the advances, challenges, and opportunities of EGFR PET biomarkers relate to this process on their way to qualification for routine clinical practice.

• atp-binding cassette subfamily b member 1
• case report
• cyp2d6
• dacomitinib
• drug-induced liver injury
• intrahepatic cholestasis

• Aged
• Bilirubin
• Carcinoma, Non-Small-Cell Lung/therapy
• Chemical and Drug Induced Liver Injury/etiology
• Chemical and Drug Induced Liver Injury/therapy
• Cholestasis, Intrahepatic/chemically induced
• Cholestasis, Intrahepatic/genetics
• Cholestasis, Intrahepatic/therapy
• Cytochrome P-450 CYP2D6
• Female
• Humans
• Lung Neoplasms/therapy
• Plasma Exchange
• Quinazolinones

• EGFR
• NSCLC
• Nazartinib
• Third-generation EGFR-TKI
• Treatment-naive

Objective: Dacomitinib has been approved for non-small-cell lung cancer (NSCLC) patients harboring classical epidermal growth factor receptor (EGFR) mutations; however, clinical evidence of its activity on major uncommon EGFR mutations is currently limited.

Materials and methods: This was a dual-center, single-arm, ambispective cohort study in China. Patients with histologically confirmed metastatic or recurrent NSCLC harboring major uncommon EGFR mutations were eligible for the study. The objective response rate and disease control rate were determined by RECIST 1.1 every 1–2 months. Adverse events were assessed by CTCAE 5.0.

Results: In total, 32 NSCLC patients were enrolled between July 2020 and January 2022, and 18 (56.3%) patients received dacomitinib as first-line therapy. Median age was 64 years, and 20 (62.5%) were female. The mutations identified were G719X (n = 24; 75%), followed by L861X (n = 10; 31.3%), and S768I (n = 8; 25%). In the first-line setting, 72.2% of patients (13/18) had a confirmed partial response and 100% (18/18) had disease control, and the median progression-free survival (PFS) and overall survival (OS) were unreached. In the whole cohort, 56.3% of patients (18/32) had a confirmed partial response and 90.6% (29/32) had disease control, and the median PFS was 10.3 months (95% confidence interval, 6.1–14.5) and the median OS was 36.5 months. Except for one case not available for brain re-evaluation, control of the intracranial metastases was observed in 13 patients (13/14, 92.9%). No grade 4–5 adverse events (AEs) occurred, but all patients had grade 1–2 AEs, and 12.5% (4/32) patients required a dosage reduction due to intolerable AEs.

Conclusions: Dacomitinib demonstrated favorable activity with manageable toxicity in patients with NSCLC harboring major uncommon EGFR mutations.

• National Natural Science Foundation of China

Patients with lung cancer benefit from more effective treatments, such as targeted therapies, and the overall survival has increased in the past decade. However, the efficacy of targeted therapies is limited due to the emergence of resistance. Growing evidence suggests that resistances may arise from a small population of drug-tolerant persister (DTP) cells. Understanding the mechanisms underlying DTP survival is therefore crucial to develop therapeutic strategies to prevent the development of resistance. Herein, we propose an overview of the current scientific knowledge about the characterisation of DTP, and summarise the new therapeutic strategies that are tested to target these cells.

Lung cancer is the leading cause of cancer-related deaths among men and women worldwide. Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are effective therapies for advanced non-small-cell lung cancer (NSCLC) patients harbouring EGFR-activating mutations, but are not curative due to the inevitable emergence of resistances. Recent in vitro studies suggest that resistance to EGFR-TKI may arise from a small population of drug-tolerant persister cells (DTP) through non-genetic reprogramming, by entering a reversible slow-to-non-proliferative state, before developing genetically derived resistances. Deciphering the molecular mechanisms governing the dynamics of the drug-tolerant state is therefore a priority to provide sustainable therapeutic solutions for patients. An increasing number of molecular mechanisms underlying DTP survival are being described, such as chromatin and epigenetic remodelling, the reactivation of anti-apoptotic/survival pathways, metabolic reprogramming, and interactions with their micro-environment. Here, we review and discuss the existing proposed mechanisms involved in the DTP state. We describe their biological features, molecular mechanisms of tolerance, and the therapeutic strategies that are tested to target the DTP.

• EGFR-TKI
• drug-tolerant persisters
• lung cancer
• targeted therapies

Phenotypical screening is a widely used approach in drug discovery for the identification of small molecules with cellular activities. However, functional annotation of identified hits often poses a challenge. The development of small molecules with narrow or exclusive target selectivity such as chemical probes and chemogenomic (CG) libraries, greatly diminishes this challenge, but non-specific effects caused by compound toxicity or interference with basic cellular functions still pose a problem to associate phenotypic readouts with molecular targets. Hence, each compound should ideally be comprehensively characterized regarding its effects on general cell functions. Here, we report an optimized live-cell multiplexed assay that classifies cells based on nuclear morphology, presenting an excellent indicator for cellular responses such as early apoptosis and necrosis. This basic readout in combination with the detection of other general cell damaging activities of small molecules such as changes in cytoskeletal morphology, cell cycle and mitochondrial health provides a comprehensive time-dependent characterization of the effect of small molecules on cellular health in a single experiment. The developed high-content assay offers multi-dimensional comprehensive characterization that can be used to delineate generic effects regarding cell functions and cell viability, allowing an assessment of compound suitability for subsequent detailed phenotypic and mechanistic studies.

• cell cycle
• chemogenomics
• high content imaging
• machine learning
• phenotypic screening

• Dacomitinib
• HPLC-MS/MS
• Human plasma
• O-desmethyl dacomitinib

• I-125 radioactive seed
• anlotinib
• bone metabolism
• lung cancer

• Non-small cell lung cancer
• T790M epidermal growth factor receptor mutation
• osimertinib
• real-world data
• tyrosine kinase inhibitor

We report a subgroup analysis of afatinib with respect to its efficacy, safety, and the long‐term survival of patients in a Named Patient Use program at a single institution.

We analyzed 60 patients with stage IV non‐small cell lung cancer (NSCLC) who had been treated with ≥1 line of platinum‐based chemotherapy and had activating epidermal growth factor receptor (EGFR) mutations or disease control for ≥6 months with prior EGFR inhibitors. Afatinib was started on a daily dose of 50 mg, which was decreased according to the adverse events and tolerability.

A total of 13 patients achieved partial remission, whereas 33, 12, and two showed stable disease, had progression, and were not evaluable, respectively, resulting in an objective response rate and disease control rate of 21.7% and 76.7%, respectively. The median progression‐free survival (PFS) was 5.4 (95% confidence interval [CI]: 4.0–7.7) months and median overall survival (OS) was 10.1 (8.5–13.6) months. Toxicities leading to drug discontinuation were experienced by four patients (6.7%). Grade 3 diarrhea occurred in 10 patients (16.7%), and afatinib dose reductions were required in 35 patients. The PFS and OS were significantly longer for patients whose dose was reduced to 40 or 30 mg than for those without dose reduction (7.0 vs 3.1 months and 13.5 vs 8.1 months, respectively, p < 0.05).

The efficacy of afatinib was similar to that identified in the global data without unexpected adverse events. Survival analyses support the currently approved dose of afatinib as first‐line treatment for NSCLC.

• EGFR
• afatinib
• carcinoma, non-small-cell lung

• 1,2,3-Triazole
• Anticancer
• Apoptosis
• Cell cycle
• EGFR
• Icotinib

• Lung cancer
• Target identification

Systemic treatment of advanced non-small cell lung cancer (NSCLC) has undergone remarkable changes in the last decade, with the introduction of targeted therapies and immunotherapy. The identification of activating mutations in the epidermal growth factor receptor (EGFR) gene (deletions in exon 19 [Del19] and point mutation L858R in exon 21) has been the first important step toward molecularly guided precision therapy in lung cancer. Several randomized trials comparing EGFR tyrosine kinase inhibitors (TKIs) (gefitinib, erlotinib, and afatinib) to standard chemotherapy in first-line treatment of advanced EGFR-mutant NSCLC showed significant improvement in progression-free survival (PFS) and in response rate, with lower rates of adverse events (AEs) and better symptom control. However, none of these trials showed significant improvement in overall survival (OS). Despite impressive responses with EGFR-TKI, disease invariably progresses after 9 to 13 months, due to acquired resistance. Dacomitinib is a potent, irreversible, highly selective, second-generation EGFR-TKI, which inhibits the signaling from both heterodimers and homodimers of all the members of the human epidermal growth factor receptor (HER) family. Here, we review the clinical development of dacomitinib from phase I to phase III, with particular attention to its toxicity and on its activity on T790M mutation. Then, we critically examine the results of ARCHER 1050, a study that was crucial for Food and Drug Administration (FDA) approval. ARCHER 1050 was the first randomized phase III study comparing dacomitinib with gefitinib, in first-line treatment of patients with advanced EGFR-mutated NSCLC. Dacomitinib was superior to gefitinib in terms of primary end-point (14.7 vs 9.2 months) and OS (34.1 vs 26.8 months). The incidence of diarrhea, skin rash, mucositis and, consequently, dose reductions was higher with dacomitinib, while hepatic toxicity was higher with gefitinib. Dacomitinib constitutes one of the standard first-line options in patients with advanced EGFR-mutated NSCLC.

Point your SmartPhone at the code above. If you have a QR code reader the video abstract will appear. Or use:

https://youtu.be/nEFa8z6JeRU

• EGFR
• NSCLC
• dacomitinib
• epidermal growth factor receptor
• non-small cell lung cancer
• pan-HER inhibitor
• second-generation TKI

• TKI
• dacomitinib
• first-line treatment
• review

• Dacomitinib
• EGFR mutations
• irreversible inhibitor
• non-small cell lung cancer
• tyrosine kinase inhibitors

• Dacomitinib
• Pancreatic ductal adenocarcinoma
• Radio-sensitivity
• The ERBB family

• Apoptosis/drug effects
• Carcinoma, Pancreatic Ductal/drug therapy
• Carcinoma, Pancreatic Ductal/pathology
• Cell Line, Tumor
• Cell Movement/drug effects
• Cell Proliferation/drug effects
• Cell Survival/drug effects
• ErbB Receptors/antagonists & inhibitors
• ErbB Receptors/metabolism
• Humans
• Models, Biological
• Neoplasm Invasiveness
• Pancreatic Neoplasms/drug therapy
• Pancreatic Neoplasms/pathology
• Quinazolinones/pharmacology
• Quinazolinones/therapeutic use
• Radiation Tolerance

• N/A Hematology/Oncology and Stem Cell Transplantation Research Center, Shariati Hospital, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran

• EGFR
• NSCLC
• dacomitinib
• dose
• first-line

Lung cancer is the leading cause of deaths related to cancer and accounts for more than a million deaths per year. Various new strategies have been developed and adapted for treatment; still the survival for 5 years is just 16% in patients with non‐small cell lung cancer (NSCLC). Most of these strategies to combat NSCLC whether it is a drug molecule or immunotherapy/vaccine candidate require a big cost and time. Integration of computational modeling with systems biology has opened new avenues for understanding complex cancer biology. Resolving the complex interactions of various pathways and their crosstalk leading to oncogenic changes could identify new therapeutic targets with lesser cost and time. Herein, this review provides an overview of various aspects of NSCLC along with available strategies for its cure concluding with our insight into how systems approach could serve as a therapeutic intervention dissecting the immunologic parameters and cross talk between various pathways involved.

• EGFR
• IL-1RB
• MAPK
• NF-kB
• NSCLC
• systems biology

• Animals
• Antineoplastic Agents, Immunological/therapeutic use
• Cancer Vaccines/therapeutic use
• Carcinoma, Non-Small-Cell Lung/diagnosis
• Carcinoma, Non-Small-Cell Lung/genetics
• Carcinoma, Non-Small-Cell Lung/immunology
• Carcinoma, Non-Small-Cell Lung/therapy
• Cytokines/immunology
• Humans
• Immunotherapy
• Lung Neoplasms/diagnosis
• Lung Neoplasms/genetics
• Lung Neoplasms/immunology
• Lung Neoplasms/therapy

• adverse event management
• dacomitinib
• non-small-cell lung cancer

• Gefitinib
• afatinib
• dacomitinib
• epidermal growth factor receptor (EGFR)
• erlotinib
• icotinib
• non-small cell lung cancer (NSCLC)

• EGFR
• NSCLC
• PI3K
• mTOR
• molecular target

• Anticancer
• EGFR
• Pyrazoline
• Quinoline
• Thiazole

• Cancer
• Pan-HER
• Target therapy

• cancer
• platelets
• signaling
• therapy
• tyrosine kinase inhibitor

• Antineoplastic Agents/adverse effects
• Antineoplastic Agents/pharmacology
• Antineoplastic Agents/therapeutic use
• Blood Platelets/drug effects
• Drug Resistance, Neoplasm
• Humans
• Interleukin-6/biosynthesis
• Molecular Targeted Therapy/adverse effects
• Neoplasm Metastasis
• Neoplasm Proteins/antagonists & inhibitors
• Neoplasm Proteins/physiology
• Neoplasms/blood
• Neoplasms/drug therapy
• Neoplasms/enzymology
• Neovascularization, Pathologic/etiology
• Neovascularization, Pathologic/physiopathology
• Oncogene Proteins, Fusion/antagonists & inhibitors
• Oncogene Proteins, Fusion/physiology
• Platelet Activation/drug effects
• Platelet Activation/physiology
• Protein Kinase Inhibitors/adverse effects
• Protein Kinase Inhibitors/pharmacology
• Protein Kinase Inhibitors/therapeutic use
• Protein-Tyrosine Kinases/antagonists & inhibitors
• Protein-Tyrosine Kinases/physiology
• Receptor Protein-Tyrosine Kinases/antagonists & inhibitors
• Receptor Protein-Tyrosine Kinases/physiology
• Thrombocytosis/etiology
• Thrombophilia/chemically induced
• Thrombophilia/etiology
• Thrombophilia/prevention & control
• Thrombopoietin/biosynthesis

Non-small cell lung cancer (NSCLC) patients with EGFR mutations initially respond well to EGFR tyrosine kinase inhibitors (TKIs) but eventually exhibit acquired or innate resistance to the therapies typically due to gene mutations, such as EGFR T790M mutation or a second mutation in the downstream pathways of EGFR. Importantly, a significant portion of NSCLC patients shows TKI resistance without any known mechanisms, calling more comprehensive studies to reveal the underlying mechanisms. Here, we investigated a synthetic lethality with gefitinib using a genome-wide RNAi screen in TKI-resistant EGFR-mutant NSCLC cells, and identified RNF25 as a novel factor related to gefitinib resistance. Depletion of RNF25 expression substantially sensitized NSCLC cells to gefitinib treatment, while forced expression of RNF25 augmented gefitinib resistance in sensitive cells. We demonstrated that RNF25 mediates NF-κB activation in gefitinib-treated cells, which, in turn, induces reactivation of ERK signal to cause the drug resistance. We identified that the ERK reactivation occurs via the function of cytokines, such as IL-6, whose expression is transcriptionally induced in a gefitinib-dependent manner by RNF25-mediated NF-κB signals. These results suggest that RNF25 plays an essential role in gefitinib resistance of NSCLC by mediating cross-talk between NF-κB and ERK pathways, and provide a novel target for the combination therapy to overcome TKI resistance of NSCLC.

• EGFR
• EGFR C797S
• L858R
• Non small cell lung cancer
• T790M
• TMLR
• WT EGFR

• Allosteric Regulation/drug effects
• Benzeneacetamides/chemistry
• Benzeneacetamides/pharmacology
• Binding Sites/drug effects
• Carcinoma, Non-Small-Cell Lung/drug therapy
• Carcinoma, Non-Small-Cell Lung/metabolism
• Drug Resistance, Neoplasm/drug effects
• Drug Resistance, Neoplasm/genetics
• Enzyme Activation/drug effects
• ErbB Receptors/antagonists & inhibitors
• ErbB Receptors/genetics
• ErbB Receptors/metabolism
• Glucokinase/metabolism
• Humans
• Lung Neoplasms/drug therapy
• Lung Neoplasms/metabolism
• Molecular Docking Simulation
• Molecular Structure
• Mutation
• Protein Kinase Inhibitors/chemistry
• Protein Kinase Inhibitors/pharmacology
• Thiazoles/chemistry
• Thiazoles/pharmacology