Receptor Tyrosine Kinase Inhibitor Research Articles

Exploring the action mechanism of Oxalis corniculata L. decoction in treating osteoarthritis utilizing liquid chromatography-mass spectrometry technology combined with network pharmacology.

This study aimed to identify the chemical constituents of Oxalis corniculata L. decoction. Furthermore, the mechanism of action of O corniculata L. decoction in treating osteoarthritis (OA) was investigated utilizing network pharmacology. The chemical composition of the O corniculata L. decoction was analyzed by employing UHPLC-Q-Exactive-MS/MS. Subsequently, a "compound-target-pathway" network was established through network pharmacology, offering a novel approach to identify the molecular mechanism underlying the treatment of OA with O corniculata L. decoction. Ultimately, the molecular docking technique was employed to validate the binding ability of the active ingredients with therapeutic targets. A total of 539 compounds were identified in O corniculata L. decoction. Topological analysis of the protein-protein interaction network indicated that compounds, including guanosine, naringenin-7-O-beta-D-glucuronide, noroxyhydrastinine, and chrysophanol 8-O-glucoside, have therapeutic potential for OA. In addition, GAPDH, TNF, TP53, epidermal growth factor receptor, and ESR1 may be key targets for the treatment of OA, primarily involving lipid and atherosclerosis, cellular senescence, IL-17 signaling pathway, and epidermal growth factor receptor tyrosine kinase inhibitor resistance signaling pathways. This method preliminarily identified the chemical composition of O corniculata L. decoction and predicted the active ingredients, potential targets, and signaling pathways of O corniculata L. decoction in treating OA. The findings of this research revealed the potential function of O corniculata L. decoction in anti-inflammation, alongside its ability to promote osteoblast proliferation and differentiation, providing new ideas for the processing of O corniculata L. herbs and related drug development.

3,3’4-trimethoxy-4’-rutinosylellagic acid and its acetylated derivative: Antioxidant activity and antiproliferative effects on breast cancer cells and molecular docking study

Cancers account for many deaths worldwide and natural compounds and their derivatives are interesting chemotherapeutic agents for cancer drug development. In this study, a natural compound 3,3’4-trimethoxy-4’-rutinosylellagic acid (TR2) and its acetylated derivative 3,3’4-trimethoxy-4’-hexaacetylrutinosylellagic acid (TR22) were evaluated for their antioxidant and anticancer effects against estrogen sensitive (MCF-7) and estrogen non-sensitive (MDA-MB 231) breast adenocarcinoma. In the β-Carotene-linoleic acid assay, DPPH• radical scavenging and CUPRAC assay, the compound TR2 had better activity than the standard α-Tocopherol, while in the ABTS•+ assay, it was more active than both standards α- α-Tocopherol and BHA. Both compounds had good antioxidant effects with TR2 being more active than TR22. Both compounds inhibited growth of breast carcinoma cells when compared to the untreated controls after 72 h. Compound TR22 significantly (p < 0.001) inhibited proliferation of both MCF-7 and MDA-MB 231 breast carcinoma cell lines suggesting that acetylation reaction improves inhibition of breast cancer cells growth. On the contrary, TR2 exhibited better inhibitory effect of clone formation than TR22 suggesting that acetylation reduces the activity in this assay. Both compounds inhibited migration of the cancer cells when compared to the untreated control cells and compound TR2 exhibited greater cellular anti-migration effect than TR22 at the same concentration and after the same period of incubation. Molecular docking studies supplemented the results and revealed that TR2 and TR22 had appreciable interactions with tyrosine kinase with negative binding energies suggesting that they are potent receptor tyrosine kinase inhibitors which can impede on cancer progression.

BIN1 deficiency enhances ULK3-dependent autophagic flux and reduces dendritic size in mouse hippocampal neurons

ABSTRACT Genome-wide association studies identified variants around the BIN1 (bridging integrator 1) gene locus as prominent risk factors for late-onset Alzheimer disease. In the present study, we decreased the expression of BIN1 in mouse hippocampal neurons to investigate its neuronal function. Bin1 knockdown via RNAi reduced the dendritic arbor size in primary cultured hippocampal neurons as well as in mature Cornu Ammonis 1 excitatory neurons. The AAV-mediated Bin1 RNAi knockdown also generated a significant regional volume loss around the injection sites at the organ level, as revealed by 7-Tesla structural magnetic resonance imaging, and an impaired spatial reference memory performance in the Barnes maze test. Unexpectedly, Bin1 knockdown led to concurrent activation of both macroautophagy/autophagy and MTOR (mechanistic target of rapamycin kinase) complex 1 (MTORC1). Autophagy inhibition with the lysosome inhibitor chloroquine effectively mitigated the Bin1 knockdown-induced dendritic regression. The subsequent molecular study demonstrated that increased expression of ULK3 (unc-51 like kinase 3), which is MTOR-insensitive, supported autophagosome formation in BIN1 deficiency. Reducing ULK3 activity with SU6668, a receptor tyrosine kinase inhibitor, or decreasing neuronal ULK3 expression through AAV-mediated RNAi, significantly attenuated Bin1 knockdown-induced hippocampal volume loss and spatial memory decline. In Alzheimer disease patients, the major neuronal isoform of BIN1 is specifically reduced. Our work suggests this reduction is probably an important molecular event that increases the autophagy level, which might subsequently promote brain atrophy and cognitive impairment through reducing dendritic structures, and ULK3 is a potential interventional target for relieving these detrimental effects.

Endothelial-to-mesenchymal transition enhances permissiveness to AAV vectors in cardiac endothelial cells

A major obstacle in inducing therapeutic angiogenesis in the heart is inefficient gene transfer to endothelial cells. Here, we identify compounds able to enhance permissiveness of cardiac endothelial cells to AAV vectors, which stand as ideal tools for in vivo gene delivery. We screened a library of >1500 FDA-approved drugs, in combination with AAV vectors, in cardiac endothelial cells. Among the top drugs increasing AAV-mediated transduction we found vatalanib, an inhibitor of multiple tyrosine kinase receptors. The increased AAV transduction efficiency by vatalanib was paralleled by the induction of endothelial to mesenchymal transition, as documented by decreased endothelial and increased mesenchymal marker expression. Induction of endothelial to mesenchymal transition by other strategies similarly increased EC permissiveness to AAV vectors. In vivo injection of AAV vectors in the heart after myocardial infarction resulted in the selective transduction of cells undergoing endothelial to mesenchymal transition, which is known to happen transiently after cardiac ischemia. Collectively, these results point to endothelial to mesenchymal transition as a mechanism improving AAV transduction in cardiac endothelial cells, with implications for both basic research and the induction of therapeutic angiogenesis in the heart.

Simultaneous Determination of Icotinib, Osimertinib, Aumolertinib, and Anlotinib in Human Plasma for Therapeutic Drug Monitoring by UPLC-MS/MS

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) such as icotinib, osimertinib, and aumolertinib have emerged as promising treatment options for EGFR mutated Non-small cell lung cancer (NSCLC) patients. Additionally, anlotinib, an anti-angiogenic agent targeting VEGFR, FGFR, and PDGFR, has been used in combination with EGFR-TKIs in NSCLC cases. A method utilizing ultrahigh performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was developed and validated for quantifying icotinib, osimertinib, aumolertinib and anlotinib simultaneously in clinical TDM. The chromatographic separation was performed using a Kinetex C18 column (100mm × 2.1mm) and an elution gradient of ammonium acetate in water acidified with 0.1% formic acid and in acetonitrile. The assay was validated over a linear range of 4–2,000ng/mL for icotinib, 2-1,000ng/mL for osimertinib, 1–500ng/mL for aumolertinib, and 0.8–400ng/mL for anlotinib, following the guidelines on bioanalytical methods by FDA. The quantification method exhibited satisfactory performance in terms of selectivity, accuracy (from 91.3% to 107%), precision (intra- and inter-day coeffficients of variation ranged from 0.944% to 7.48%), linearity, recovery (from 86.0% to 91.9%), matrix effect (IS-normalized matrix factors were from 96.7% to 102%), and stability. Overall, the method proved to be sensitive, reliable, and straightforward, enabling successful simultaneous determination of blood concentrations of icotinib, osimertinib, aumolertinib, and anlotinib in patients. The validity of the method has been confirmed across various instruments.

Lazertinib in EGFR-Variant Non–Small Cell Lung Cancer With CNS Failure to Prior EGFR Tyrosine Kinase Inhibitors

EGFR-variant non-small cell lung cancer (NSCLC) is associated with a high rate of central nervous system (CNS) metastases, even with treatment with first-generation or second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). To investigate CNS activity with lazertinib, a third-generation EGFR TKI. This multicenter single-arm, phase 2 nonrandomized controlled trial was conducted in South Korea and included patients with EGFR-variant NSCLC who had asymptomatic or mildly symptomatic brain metastases after unsuccessful treatment with first-generation or second-generation EGFR TKIs. Data were collected from June 2021 to April 2022, with a data cutoff date of December 15, 2022. Lazertinib, 240 mg, once daily. The primary end point was intracranial objective response rate (iORR) in the evaluable population according to the Response Evaluation Criteria in Solid Tumours version 1.1 assessed by the investigators. Secondary end points included intracranial progression-free survival (iPFS) and iORR in patients with T790M-negative disease and isolated CNS progression as well as overall ORR, duration of response, intracranial duration of response, disease control rate, overall survival, cerebrospinal fluid penetration of lazertinib, and safety. Among 40 included patients, 25 (63%) were women, and the median (range) age was 63 (29-85) years. A total of 38 patients were evaluable for tumor response, including 12 patients with leptomeningeal metastases. At data cutoff, the median (range) follow-up was 13.6 (2.9-17.7) months. The iORR for the evaluable population was 55% (21 of 38; 95% CI, 38.3-71.4); for patients with T790M-positive disease, 80% (4 of 5; 95% CI, 28.4-99.5); for patients with T790M-negative disease, 43% (9 of 21; 95% CI, 21.8-66.0); and for patients with T790M-unknown disease, 67% (8 of 12; 95% CI, 34.9-90.1). The median iPFS was 15.8 months (95% CI, 15.2-not reached) for the evaluable population, 15.2 months (95% CI, 4.2-not reached) for the T790M-positive subgroup, 15.4 months (95% CI, 7.9-not reached) for the T790M-negative subgroup, and 18.0 months (95% CI, 3.9-not reached) for the T790M-unknown subgroup. The cerebrospinal fluid penetration rate of lazertinib was 46.2% (95% CI, 10.0-49.6), providing further support for its mechanism of intracranial response. Most adverse events were grade 1 or 2. In this study, lazertinib had substantial CNS activity, regardless of T790M status, against the progression of intracranial metastases with or without leptomeningeal metastases after unsuccessful treatment with first-generation or second-generation EGFR TKIs in patients with metastatic EGFR-variant NSCLC. These results suggest that using lazertinib instead of brain local treatment could be a potential strategy in patients with EGFR-variant NSCLC whose CNS metastases progressed after prior EGFR TKI treatment. ClinicalTrials.gov Identifier: NCT05326425.

Complete response in a lung adenocarcinoma with pleural metastases initially treated with gefitinib and switched to osimertinib after cerebral oligo-progression with unknown T790M mutation: a case report and review of literature

BackgroundFirst- and second-generation anti-epithelial growth factor receptor tyrosine kinase inhibitors have shown great efficacy in the treatment of advanced adenocarcinoma with epithelial growth factor receptor mutations, but this efficacy is limited by certain resistance mechanisms, in particular the T790M mutation, which must be screened before second-line treatment with osimertinib is indicated. The search for this mutation is sometimes difficult, especially in cases of intracranial relapse, through this case report we attempt to discuss the possibility of initiating treatment with osimertinib despite an unknown T790M mutation in such situation.Case reportWe present the case of a 70-year-old Moroccan male patient diagnosed with non-small cell lung carcinoma initially metastatic to the pleura with an epithelial growth factor receptor mutation who received gefitinib in first line with a complete response, he subsequently presented with cerebral oligo-progression with extra cranial stability. The patient was started on osimertinib with unknown T790M status, as it was impossible to perform a cerebral biopsy, the evolution was characterized by a partial response followed by stereotactic radiotherapy then a complete response for 2 years.ConclusionWe can discuss osimertinib as an option for patients with stage IV non-small cell lung cancer with brain oligo-progression on prior tyrosine kinase inhibitors and unknown T790M status, further studies are needed in this area.

Predicting Survival of Metastatic Clear Cell Renal Cell Cancer Treated with VEGFR-TKI-Based Sequential Therapy.

(1) Objective: To develop a clinically useful nomogram that may provide a more individualized and accurate estimation of cancer-specific survival (CSS) for patients with clear-cell (CC) metastatic renal cell carcinoma (mRCC) treated with nephrectomy and vascular endothelial growth factor receptor-tyrosine kinase inhibitor (VEGFR-TKI)-based sequential therapy. (2) Methods: A prospectively maintained database of 145 patients with mRCC treated between 2008 and 2018 was analyzed to predict the CSS of patients receiving sunitinib and second- and third-line therapies according to current standards of practice. A nomogram based on four independent clinical predictors (Eastern Cooperative Oncology Group status, International Metastatic RCC Database Consortium score, the Morphology, Attenuation, Size and Structure criteria and Response Evaluation Criteria in Solid Tumors response criteria) was calculated. The corresponding 1- to 10-year CSS probabilities were then determined from the nomogram. (3) Results: The median age was 60 years (95% CI 57.9-61.4). The disease was metastatic at diagnosis in 59 (40.7%), and 86 (59.3%) developed metastasis during follow-up. Patients were followed for a median 48 (IQR 72; 95% CI 56-75.7) months after first-line VEGFR-TKI initiation. The concordance probability estimator value for the nomogram is 0.778 ± 0.02 (mean ± SE). (4) Conclusions: A nomogram to predict CSS in patients with CC mRCC that incorporates patient status, clinical risk classification and response criteria to first-line VEGFR-TKI at 3 months is presented. This new tool may be useful to clinicians assessing the risk and prognosis of patients with mRCC.

Advanced Renal Cell Cancer Combination Immunotherapy Clinical Trial (ARCITECT; HCRN GU 22-587)

Abstract Background First-line treatment for patients with metastatic clear cell renal cell carcinoma (mccRCC) often includes an anti-PD1 inhibitor in combination with either an anti-CTLA inhibitor (IO/IO) or a VEGF receptor tyrosine kinase inhibitor (TKI) (IO/TKI). Although some patients treated with nivolumab/ipilimumab (Nivo/Ipi) (IO/IO) experience durable responses leading to treatment free intervals, over two-thirds experience disease progression. Resistance to Nivo (anti-PD1) monotherapy has been associated with increased presence of a subpopulation of Tregs in the tumor microenvironment. Botensilimab (Bot) is an IO agent that leverages novel FcyR-associated mechanisms of action to enhance T cell priming, deplete intratumoral Tregs and enhance myeloid activation. Combination botensilimab/balstilimab (Bot/Bal) (anti-CTLA/anti-PD1) has shown impressive anti-tumor activity in diseases where Nivo/Ipi has shown little to no efficacy. Methods ARCITECT is a phase II, multicenter study evaluating the efficacy and safety of Bot/Bal relative to Nivo/Ipi. Patients with mccRCC (favorable, intermediate, or poor risk), no prior systemic therapy (including adjuvant or neoadjuvant), and at least one measurable lesion as defined by RECIST 1.1 are eligible for enrollment. 120 patients will be randomized in a 2:1 fashion to Arm A (Bot/Bal induction followed by Bal maintenance) or Arm B (Nivo/Ipi induction followed by Nivo maintenance) each for a maximum of 2 years. Stratification factors include IMDC risk groups and sarcomatoid histology. The primary endpoint is overall response rate (ORR) per RECIST 1.1. We hypothesize that Bot/Bal will lead to a superior ORR (55%) relative to Nivo/Ipi (40%). This trial has &amp;gt; 90% power to detect the alternative hypothesis while maintaining a one-sided significance level of not more than 0.10 using the exact binomial. The study will be monitored for early stopping in favor of the null hypothesis based on a Simon’s two stage design. In the first stage, 69 patients will be enrolled (Arm A:46 and Arm B:23). If at the end of the first stage, Arm A has either at least 18/42 (42.8%) of eligible patients responding or an ORR at least numerically equivalent to that for eligible patients in Arm B, then the trial will progress to the second stage. The primary endpoint will be met if there are 38/80 responders (ORR &amp;gt; 47.5%) in Arm A. Key secondary endpoints include landmark progression-free survival, treatment-free survival and rates of immune-related adverse events. Correlative studies will explore immune and molecular predictors of response and resistance to IO/IO in tumor and blood. Clinical trial information: NCT05928806. Results

Central serous chorioretinopathy secondary to drugs: a real-world pharmacovigilance study of the FDA adverse event reporting system (FAERS)

ABSTRACT Background The objective of this study was to evaluate the reporting associations between Central serous chorioretinopathy (CSCR) and many available drugs using FAERS. Research design and methods FAERS reports from 2004 to 2023 were included in the study. The Medical Dictionary for Regulatory Activities (MedDRA) was used to identify CSCR cases. Reporting odds ratios (RORs) and corresponding 95% confidence intervals (CIs) for the reporting associations between available drugs and CSCR were calculated. A reporting association was considered statistically significant when the lower limit of the 95% CI was > 1.0. Results There were 1002 reports of 110 drugs with suspected drug-associated CSCR based on the ‘primary suspects’ role code in the FAERS database found to have statistically significant signals. Among the top 20 ROR drugs, the most frequently reported drugs were dermatological drugs (ATC:D, 210 cases, 64.41%), followed by antitumor agents and immunological agents (ATC:L,77 cases, 23.62%), Systemic Hormonal Preparations, Excl. Sex hormones and Insulins (ATC:H, 19 cases, 5.80%) and sensory organ drugs (ATC:S, 9 cases, 2.76%). The top 3 drugs associated with CSCR were Prednisolone (144 cases, 44.17%), Fluticasone (29 cases, 8.90%), and Methylprednisolone (27 cases, 8.28%). Conclusions This is the first real-world study using FAERS database to investigate drug-induced CSCR. Clinicians and pharmacist must keep in mind CSCR is a serious ocular complication associated with glucocorticoids, tyrosine kinase receptor inhibitor, and other drugs that can cause CSCR.

TONSL promotes lung adenocarcinoma progression, immune escape and drug sensitivity.

The tonsoku-like DNA repair protein (TONSL) encoded by the TONSL gene, located on chromosome 8q24.3, is crucial for repairing DNA double-strand breaks through homologous recombination. However, TONSL overexpression in lung adenocarcinoma (LUAD) promotes tumor development, leading to a poor prognosis. TONSL was verified as a reliable prognostic marker for LUAD using bioinformatics, and clinical features related to LUAD prognosis were screened from the TCGA database to establish the relationship between risk factors and TONSL expression. In addition, TONSL expression in normal and LUAD tissues was verified using real-time quantitative polymerase chain reaction and immunohistochemistry. To elucidate the possible functions of TONSL, TONSL-related differentially expressed genes were screened, and functional enrichment analysis was performed. Subsequently, siRNA was used to knock down TONSL expression in lung cancer cells for cytobehavioral experiments. The effects of TONSL expression on tumor immune escape were analyzed using the ESTIMATE algorithm and tumor immune-infiltration analysis. In addition, the half-maximal inhibitory concentration of LUAD with varying TONSL expression levels in response to first-line chemotherapeutic drugs and epidermal growth factor receptor-tyrosine kinase inhibitors was analyzed for drug sensitivity. Up-regulation of TONSL in LUAD promotes the proliferation, migration, and invasion of lung cancer cells, thereby contributing to a poor prognosis. Furthermore, TONSL overexpression promotes immune escape and drug sensitivity in LUAD. TONSL serves as a reliable prognostic marker for LUAD, and its up-regulation is associated with increased immune escape and drug sensitivity. These findings suggest that TONSL holds potential as a novel therapeutic target for LUAD.

Activation of Hepatocyte Growth Factor/MET Signaling as a Mechanism of Acquired Resistance to a Novel YAP1/TEAD Small Molecule Inhibitor.

Many tumor types harbor alterations in the Hippo pathway, including mesothelioma, where a high percentage of cases are considered YAP1/TEAD dependent. Identification of autopalmitoylation sites in the hydrophobic palmitate pocket of TEADs, which may be necessary for YAP1 protein interactions, has enabled modern drug discovery platforms to generate compounds that allosterically inhibit YAP1/TEAD complex formation and transcriptional activity. We report the discovery and characterization of a novel YAP1/TEAD inhibitor MRK-A from an aryl ether chemical series demonstrating potent and specific inhibition of YAP1/TEAD activity. In vivo, MRK-A showed a favorable tolerability profile in mice and demonstrated pharmacokinetics suitable for twice daily oral dosing in preclinical efficacy studies. Importantly, monotherapeutic targeting of YAP1/TEAD in preclinical models generated regressions in a mesothelioma CDX model; however, rapid resistance to therapy was observed. RNA-sequencing of resistant tumors revealed mRNA expression changes correlated with the resistance state and a marked increase of hepatocyte growth factor (HGF) expression. In vitro, exogenous HGF was able to fully rescue cytostasis induced by MRK-A in mesothelioma cell lines. In addition, co-administration of small molecule inhibitors of the MET receptor tyrosine kinase suppressed the resistance generating effect of HGF on MRK-A induced growth inhibition. In this work, we report the structure and characterization of MRK-A, demonstrating potent and specific inhibition of YAP1/TAZ-TEAD-mediated transcriptional responses, with potential implications for treating malignancies driven by altered Hippo signaling, including factors resulting in acquired drug resistance.

Appraisal and synthesis of novel indole-thiazole derivatives as epidermal growth factor receptor tyrosine kinase (EGFR-TK) inhibitors against resistance mutation for lung cancer treatment

Appraisal and synthesis of novel indole-thiazole derivatives as epidermal growth factor receptor tyrosine kinase (EGFR-TK) inhibitors against resistance mutation for lung cancer treatment

Outcomes in non-small cell lung cancer with uncommon epidermal growth factor receptor L858 substitutions under first-line epidermal growth factor receptor tyrosine kinase inhibitors: A large real-world cohort study.

Atypical L858R or other L858X mutations in the epidermal growth factor receptor (EGFR) gene, beyond the classical EGFRL858R mutation caused by c.2573 T > G, have been identified in non-small cell lung cancer (NSCLC), yet their genomic features and survival benefits with EGFR tyrosine kinase inhibitor (TKI) treatment have not been fully explored. We retrospectively enrolled 489 NSCLC patients with baseline tumor tissue/plasma samples carrying uncommon EGFRL858R (N = 124), EGFRL858Q/M (N = 17), or classical EGFRL858R mutations (N = 348). The comparison of molecular features was performed using treatment-naïve tumor tissues. Survival benefits and resistance mechanisms of first-line EGFR TKI treatment were studied in an advanced disease subcohort. NSCLCs harboring uncommon EGFRL858R had lower TP53 mutation prevalence (p = 0.04) and chromosome instability scores (p = 0.02) than those with classical EGFRL858R. Concomitant EGFRL861Q mutations were enriched in NSCLCs with EGFRL858Q/M (p < 0.01), with cooccurrence in those carrying EGFRL858M. Patients with uncommon EGFRL858R experienced improved progression-free survival (PFS) compared to those with classical EGFRL858R (median: 13.0 vs. 10.0 months, hazard ratio [HR]: 0.57, 95% confidence interval [CI]: 0.41-0.80). The association remained significant when adjusting for sex, age, histological subtype, TKI category, and anti-vascular therapy (HR: 0.55, 95% CI: 0.39-0.77). Furthermore, EGFRL858Q/M patients showed enhanced first-line PFS (vs. classical EGFRL858R, HR: 0.26, 95% CI: 0.10-0.67), potentially benefiting more from afatinib. Additionally, NSCLCs with uncommon EGFRL858R and classical EGFRL858R had similar resistance profiles to EGFR TKIs. In conclusion, NSCLCs carrying atypical EGFR L858 aberrations, which had fewer TP53 mutations and higher chromosome stability, exhibited improved PFS under first-line EGFR TKIs than those with the classical EGFRL858R.

Fighting the invisible foe in cancer therapy

In this issue of Cell Host & Microbe, Huang etal. determine that an oncogenic bacterium contributes to colorectal cancer progression and resistance to receptor tyrosine kinase inhibitors. These findings highlight the need for an integrative approach for cancer treatment that considers the influence of the microbiome.

Adverse Effects of Gefitinib on Skin and Colon in a Lung Cancer Mouse Model.

Gefitinib, an Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor (EGFR-TKI), frequently causes side effects when used to treat non-small cell lung cancer. The purpose of this experiment was to investigate the side effect of gefitinib on the skin and colon of mice. Male Balb/c nu-nu nude mice aged 4-5 weeks were used as xenograft tumor models, and gefitinib at 150 mg/kg and 225 mg/kg was started at 9 days after the xenograft tumor grew out. The mice's weights and tumor volumes were tracked concurrently, and the mouse skin adverse reactions and diarrhea were observed during the treatment. The animal tissues were subjected to biochemical and pathological evaluations after 14 days. Gefitinib effectively decreased the size and weight of transplanted tumors in nude mice, while also lowering body weight and raising indexes of the liver and spleen. Gefitinib could cause skin adverse reactions and diarrhea in mice. Further pathological investigation revealed tight junction- related markers in the mice's skin and colon to be reduced and macrophages and neutrophils to be increased after gefitinib treatment. The findings imply that gefitinib has negative effects on the skin and colon. Gefitinib- induced skin and colon adverse reactions in mice have been successfully modeled in this study.

Oral lichenoid drug eruption due to osimertinib for lung cancer.

Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR) are linked with side effects involving skin and mucosa. Herein, we present a unique case of oral lichenoid drug eruption (LDE) in a patient treated with osimertinib. A 75-year-old woman was diagnosed with metastatic EGFR-mutated lung adenocarcinoma, and started on osimertinib 80 mg PO daily. At 24 months of therapy, the patient developed a painful, red, and white striated oral lesion involving the left buccal mucosa and the adjacent buccal aspect of gingivae. Biopsy showed oral LDE. Causality assessment between osimertinib and the oral LDE via Naranjo Adverse Drug Reaction probability scale revealed a score of 5. Osimetinib discontinuation was not felt to be in the best interest of the patient. Therefore, diphenhydramine HCL mouthwash every 6 h PRN (before meals) was started. Spicy and hot foods were discontinued. At a four-week follow-up visit, the patient reported moderate improvement in her symptoms. Oral LDEs are considered premalignant lesions as they can transform into squamous cell carcinoma; therefore, regular follow-up is needed. Awareness of this potential side effect of osimertinib would also prevent unnecessary (and potentially costly) work-up and lead to its prompt diagnosis and treatment.

Discovery of a potent, selective, and orally available EGFR C797S mutant inhibitor (DS06652923) with in vivo antitumor activity

The C797S mutation is one of the major factors behind resistance to the third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). Herein, we describe the discovery of DS06652923, a novel, potent, and orally available EGFR-triple-mutant inhibitor. Through scaffold hopping from the previously reported nicotinamide derivative, a novel biaryl scaffold was obtained. The potency was successfully enhanced by the introduction of basic substituents based on analysis of the docking study results. In addition, the difluoromethoxy group on the pyrazole ring improved the kinase selectivity by inducing steric clash with the other kinases. The most optimized compound, DS06652923, achieved tumor regression in the Ba/F3 allograft model upon its oral administration.

Inhibition of DDR1 promotes ferroptosis and overcomes gefitinib resistance in non-small cell lung cancer

Gefitinib is an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), which serves the critical pillar for the treatment of non-small cell lung cancer (NSCLC). However, the acquired resistance remains a challenge for its clinical application, for which, practical strategies to reverse gefitinib resistance in NSCLC are necessary. Ferroptosis, a programmed cell death driven by ferritin-dependent lipid peroxidation, involves in NSCLC progression and related chemoresistance. In our previous work, the self-synthesised EGFR inhibitor Yfq07 (N4, N6-disubstituted pyrimidine-4,6-diamine derivatives) displayed a considerable inhibitory effect on NSCLC both in vitro and in vivo. Herein, we observed that Yfq07 suppressed the proliferation of PC-9GR and HCC827GR cells, two gefitinib resistance NSCLC cell lines. Mechanically, Yfq07 inhibited the phosphorylation of the Discoidin Domain Receptor 1 (DDR1), a receptor tyrosine kinase (RTK) highly expressed in multiple cancers, accompanied by downregulated miR-3648 and upregulated SOCS2. Inhibition or knockdown of DDR1 suppressed the proliferation, migration, and invasion of gefitinib-resistant NSCLC cells, and on the other hand, also downregulated miR-3648 and promoted SOCS2 expression. More specifically, miR-3648 targeted the 3’UTR segment of SOCS2 mRNA and thus affecting the P-ERK signalling pathway to regulate the malignant behaviors of gefitinib-resistant NSCLC cells. Furthermore, Yfq07 also indirectly induced the ferroptosis of gefitinib-resistant NSCLC cells via SOCS2 triggered inhibition of xCT-GPX4 pathway. In conclusion, our study indicates that DDR1 inhibitor Yfq07 promotes ferroptosis and reverses gefitinib-resistance of NSCLC through DDR1-miR-3648-SOCS2 signalling pathway, which provides insights for targeted therapy of gefitinib-resistant NSCLC and drug developments targeting ferroptosis.

PSIP1 promotes gefitinib resistance in lung adenocarcinoma by inducing the expression of WASF3 and its downstream ITGB3/AKT signaling.

Gefitinib (GR), a representative drug of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), is a key pillar in the treatment of lung adenocarcinoma (LUAD), but drug resistance is universal. Identifying the potential factors of drug resistance to GR is essential to treat patients with EGFR mutant LUAD. The GR-resistant LUAD cells were established and confirmed by MTT assay. The effects of PC4 and SRSF1 interacting protein 1 (PSIP1) on GR-resistant cell proliferation and apoptosis in vitro and in vivo were detected by colony formation, flow cytometry, tumor-bearing animal model, immunohistochemistry, and TUNEL staining. Western blotting and qPCR were used to determine the expression of relevant markers. The effect of PSIP1 on the promoter region of Wiskott-Aldrich syndrome protein family member 3 (WASF3) was detected by the dual-luciferase assay. The interaction between PSIP1 and RNA polymerase II was evaluated using ChIP-qPCR and Co-IP assays. PSIP1 was highly enriched in GR-resistant LUAD cells. Downregulation of PSIP1 expression significantly inhibited the proliferation of LUAD-resistant cells and promoted apoptosis. WASF3 was shown to have similar effects as PSIP1 in promoting drug resistance in LUAD cells. PSIP1 promoted the transcriptional activity of WASF3, which was achieved by increasing RNA polymerase II recruitment on the WASF3 promoter. Furthermore, PSIP1 positively regulated the expression of the pro-EGFR-TKI resistance factor integrin subunit beta 3 (ITGB3). Our work suggests that PSIP1 promotes resistance to GR in LUAD cells by inducing the expression of WASF3 and its downstream regulator ITGB3.