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Journal of Medical Case Reports Mar 2024In the current treatment landscape for non-small cell lung cancers, epidermal growth factor receptor-tyrosine kinase inhibitors have emerged as a well-established...
BACKGROUND
In the current treatment landscape for non-small cell lung cancers, epidermal growth factor receptor-tyrosine kinase inhibitors have emerged as a well-established treatment option for patients with advanced or metastatic disease. This is particularly true for those with commonly occurring epidermal growth factor receptor mutations. However, the therapeutic efficacy of these agents for so-called rare epidermal growth factor receptor mutations, and in particular those characterized by a high degree of complexity, such as double mutations, remains a subject of clinical uncertainty.
CASE PRESENTATION
In this context, we present the case of a 64-year-old man of Moroccan descent, a lifelong non-smoker, diagnosed with metastatic non-small cell lung cancer characterized by a complex epidermal growth factor receptor mutation encompassing L858R and S768I. The patient subsequently underwent afatinib-based treatment, showing notable clinical results. These included a remarkable overall survival of 51 months, with a median progression-free survival of more than 39 months.
CONCLUSIONS
This case report is a compelling testimony to the evolving therapeutic landscape of non-small cell lung cancers, providing valuable insight into the potential therapeutic efficacy of epidermal growth factor receptor-tyrosine kinase inhibitors in the realm of rare and complex epidermal growth factor receptor mutations.
Topics: Humans; Middle Aged; Carcinoma, Non-Small-Cell Lung; Clinical Decision-Making; ErbB Receptors; Lung Neoplasms; Mutation; Protein Kinase Inhibitors; Tyrosine Kinase Inhibitors; Uncertainty; Male
PubMed: 38494473
DOI: 10.1186/s13256-024-04422-5 -
Aging Mar 2024Inhibitors of Epidermal growth factor receptor tyrosine kinase (EGFR-TKIs) are producing impressive benefits to responsive types of cancers but challenged with drug...
Inhibitors of Epidermal growth factor receptor tyrosine kinase (EGFR-TKIs) are producing impressive benefits to responsive types of cancers but challenged with drug resistances. FHND drugs are newly modified small molecule inhibitors based on the third-generation EGFR-TKI AZD9291 (Osimertinib) that are mainly for targeting the mutant-selective EGFR, particularly for the non-small cell lung cancer (NSCLC). Successful applications of EGFR-TKIs to other cancers are less certain, thus the present pre-clinical study aims to explore the anticancer effect and downstream targets of FHND in multiple myeloma (MM), which is an incurable hematological malignancy and reported to be insensitive to first/second generation EGFR-TKIs (Gefitinib/Afatinib). Cell-based assays revealed that FHND004 and FHND008 significantly inhibited MM cell proliferation and promoted apoptosis. The RNA-seq identified the involvement of the MAPK signaling pathway. The protein chip screened PDZ-binding kinase (PBK) as a potential drug target. The interaction between PBK and FHND004 was verified by molecular docking and microscale thermophoresis (MST) assay with site mutation (N124/D125). Moreover, the public clinical datasets showed high expression of PBK was associated with poor clinical outcomes. PBK overexpression evidently promoted the proliferation of two MM cell lines, whereas the FHND004 treatment significantly inhibited survival of 5TMM3VT cell-derived model mice and growth of patient-derived xenograft (PDX) tumors. The mechanistic study showed that FHND004 downregulated PBK expression, thus mediating ERK1/2 phosphorylation in the MAPK pathway. Our study not only demonstrates PBK as a promising novel target of FHND004 to inhibit MM cell proliferation, but also expands the EGFR kinase-independent direction for developing anti-myeloma therapy.
Topics: Humans; Animals; Mice; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Protein Kinase Inhibitors; Multiple Myeloma; Molecular Docking Simulation; Drug Resistance, Neoplasm; ErbB Receptors; Extracellular Signal-Regulated MAP Kinases; Cell Proliferation; Mutation; Mitogen-Activated Protein Kinase Kinases
PubMed: 38460944
DOI: 10.18632/aging.205634 -
Cancer Treatment and Research... 2024Previous studies have identified an interaction between protein kinase inhibitors (PKIs) and proton pump inhibitors (PPIs) in patients with lung cancer. This type of...
INTRODUCTION
Previous studies have identified an interaction between protein kinase inhibitors (PKIs) and proton pump inhibitors (PPIs) in patients with lung cancer. This type of interaction may reduce the efficacy of PKIs. However, the effect of PKI-PPI interaction on patient mortality remains controversial. This study set out to determine the impact of PKI-PPI interaction on overall survival for lung cancer patients.
MATERIALS AND METHODS
This study was conducted using data from the French National Health Care Database from January 1, 2011 to December 31, 2021. We identified patients with: (i) an age equal to or greater than 18 years; (ii) lung cancer; and (iii) at least one reimbursement for one of the following drugs: erlotinib, gefitinib, afatinib and osimertinib. Patients were followed-up between the first date of PKI reimbursement and either December 31, 2021 or if they died, the date on which death occurred. The cumulative exposure to PPI duration during PKI treatment was calculated as the ratio between the number of concomitant exposure days to PKI and PPI and the number of exposure days to PKI. A survival analysis using a Cox proportional hazards model was then performed to assess the risk of death following exposure to a PKI-PPI interaction.
RESULTS
34,048 patients received at least one reimbursement for PKIs of interest in our study: 26,133 (76.8 %) were exposed to erlotinib; 3,142 (9.2 %) to gefitinib; 1,417 (4.2 %) to afatinib; and 3,356 (9.9 %) to osimertinib. Patients with concomitant exposure to PKI-PPI interaction during 20 % or more of the PKI treatment period demonstrated an increased risk of death (HR, 1.60 [95 % CI, 1.57-1.64]) compared to other patients. When this cut-off varied from 10 % to 80 %, the estimated HR ranged from 1.46 [95 % CI, 1.43-1.50] to 2.19 [95 % CI, 2.12-2.25].
DISCUSSION/CONCLUSION
In our study, an elevated risk of death was observed in patients exposed to PKI-PPI interaction. Finally, we were able to identify a dose-dependent effect for this interaction. This deleterious effect of osimertinib and PPI was revealed for the first time in real life conditions.
Topics: Humans; Lung Neoplasms; Proton Pump Inhibitors; Protein Kinase Inhibitors; Male; Female; Aged; Middle Aged; Cohort Studies; Afatinib; Aniline Compounds; Acrylamides; Aged, 80 and over; Drug Interactions; France; Adult; Gefitinib; Retrospective Studies
PubMed: 38447474
DOI: 10.1016/j.ctarc.2024.100801 -
European Journal of Cancer (Oxford,... Apr 2024The combination of gemcitabine/nab-paclitaxel is an established standard treatment in the first-line treatment of metastatic ductal adenocarcinoma of the pancreas...
PURPOSE
The combination of gemcitabine/nab-paclitaxel is an established standard treatment in the first-line treatment of metastatic ductal adenocarcinoma of the pancreas (mPDAC). Afatinib, an oral second-generation pan ErbB family tyrosine kinase inhibitor, has shown promising pre-clinical signs in the treatment of pancreatic cancer. The aim of this phase 1b trial was to determine the maximum tolerated dose (MTD) of afatinib in combination with gemcitabine/nab-paclitaxel in patients with mPDAC.
METHODS
Treatment naïve patients (≥18 years) with histologically proven mPDAC and good performance status (ECOG 0/1) were enrolled to receive gemcitabine/nab-paclitaxel in combination with afatinib. Treatment was continued until disease progression, or unacceptable toxicity. The primary endpoint MTD was determined using a 3 + 3 design. Treatment started at dose level 0 with intravenous gemcitabine/nab-paclitaxel 1000 mg/m / 125 mg/m (day 1, 8, 15 of a 28-day cycle) + oral afatinib 30 mg daily. At dose level + 1 afatinib was increased to 40 mg. Secondary endpoints included safety parameters and exploratory endpoints evaluated treatment efficacy.
RESULTS
Twelve patients were included in this trial, and 11 patients were treated and analysed in the safety and full analysis set (FAS). At dose level 0 the first three patients did not experience a dose-limiting toxicity (DLT). At dose leve (DL) + 1 two patients experienced a DLT. Accordingly, enrolment continued at DL 0 with three more patients, of which one experienced DLT (skin rash ≥ CTCAE grade 3). Seven patients (63.6%) experienced at least one treatment-emergent serious adverse event (TESAE), with four patients (36.4%) experiencing TESAEs grade 3-5 related to the study medication. In the FAS, the objective response rate (ORR) was 36.4%, median progression-free survival (PFS) was 3.5 months and median overall survival in nine evaluable patients was 7.5 months.
CONCLUSIONS
In this phase 1b clinical trial, the MTD of gemcitabine/nab-paclitaxel (1000 mg/m / 125 mg/m) and afatinib (30 mg) was established. In a cohort of 11 patients, the combination showed an acceptable safety profile.
Topics: Humans; Gemcitabine; Afatinib; Deoxycytidine; Paclitaxel; Albumins; Pancreatic Neoplasms; Treatment Outcome; Antineoplastic Combined Chemotherapy Protocols
PubMed: 38401449
DOI: 10.1016/j.ejca.2024.113926 -
Scientific Reports Feb 2024Disulfidptosis a new cell death mode, which can cause the death of Hepatocellular Carcinoma (HCC) cells. However, the significance of disulfidptosis-related Long...
Disulfidptosis a new cell death mode, which can cause the death of Hepatocellular Carcinoma (HCC) cells. However, the significance of disulfidptosis-related Long non-coding RNAs (DRLs) in the prognosis and immunotherapy of HCC remains unclear. Based on The Cancer Genome Atlas (TCGA) database, we used Least Absolute Shrinkage and Selection Operator (LASSO) and Cox regression model to construct DRL Prognostic Signature (DRLPS)-based risk scores and performed Gene Expression Omnibus outside validation. Survival analysis was performed and a nomogram was constructed. Moreover, we performed functional enrichment annotation, immune infiltration and drug sensitivity analyses. Five DRLs (AL590705.3, AC072054.1, AC069307.1, AC107959.3 and ZNF232-AS1) were identified to construct prognostic signature. DRLPS-based risk scores exhibited better predictive efficacy of survival than conventional clinical features. The nomogram showed high congruence between the predicted survival and observed survival. Gene set were mainly enriched in cell proliferation, differentiation and growth function related pathways. Immune cell infiltration in the low-risk group was significantly higher than that in the high-risk group. Additionally, the high-risk group exhibited higher sensitivity to Afatinib, Fulvestrant, Gefitinib, Osimertinib, Sapitinib, and Taselisib. In conclusion, our study highlighted the potential utility of the constructed DRLPS in the prognosis prediction of HCC patients, which demonstrated promising clinical application value.
Topics: Humans; Carcinoma, Hepatocellular; RNA, Long Noncoding; Liver Neoplasms; Prognosis; Nomograms
PubMed: 38388539
DOI: 10.1038/s41598-024-54115-8 -
Thoracic Cancer Mar 2024Skin disorders are the most common side effect associated with epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) therapy. It is important to manage...
BACKGROUND
Skin disorders are the most common side effect associated with epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) therapy. It is important to manage skin lesions. Adapalene has been used to treat skin lesions caused by EGFR-TKIs in some cases. The aim of this study was to investigate the functional mechanism of adapalene in erlotinib-induced skin disorder.
METHODS
To analyze the effect of adapalene on skin rash, afatinib and adapalene were administered to mice. The relationship between the concentration of adapalene and skin disorders was also examined by analyzing AQP3 expression. A skin lesion model was experimentally established in human skin keratinocytes (HaCaT) by using erlotinib with TNF-α and IL-1β. We used qRT-PCR to analyze chemokine-induced inflammation and western blotting to analyze the effects of adapalene on the NF-κB signaling pathway. Antimicrobial peptides and adhesion factors were also examined using qRT-PCR.
RESULTS
Mice administered 0.01% adapalene had less skin inflammation than mice treated with afatinib alone. The expression level of AQP3 decreased in an adapalene concentration-dependent manner. The mRNA levels of proinflammatory cytokines such as CCL2 and CCL27 in HaCaT cells were significantly reduced by adapalene. The expression of an antimicrobial peptide, hBD3, was upregulated after adapalene treatment. Adhesion factors, such as E-cadherin, were significantly downregulated by EGFR-TKI and significantly upregulated by adapalene treatment. Western blot analysis suggested that erlotinib-induced phosphorylation of p65 was decreased by adapalene.
CONCLUSION
We suggest that adapalene may be a possible treatment option for skin disorders induced by EGFR-TKIs.
Topics: Humans; Animals; Mice; Afatinib; Erlotinib Hydrochloride; Adapalene; ErbB Receptors; Skin Diseases; Inflammation; Protein Kinase Inhibitors; Lung Neoplasms
PubMed: 38379420
DOI: 10.1111/1759-7714.15249 -
BMC Cancer Feb 2024The irreversible epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) afatinib and dacomitinib are approved for first-line treatment of EGFR... (Observational Study)
Observational Study
The difference between dacomitinib and afatinib in effectiveness and safety in first-line treatment of patients with advanced EGFR-mutant non-small cell lung cancer: a real-world observational study.
OBJECTIVES
The irreversible epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) afatinib and dacomitinib are approved for first-line treatment of EGFR mutation-positive non-small cell lung cancer (NSCLC). We aimed to compare the efficacy and safety of afatinib and dacomitinib in this setting.
MATERIALS AND METHODS
Between September 2020 and March 2023, we retrospectively recruited patients diagnosed with advanced-stage EGFR-mutant NSCLC who were treated with first-line irreversible EGFR-TKIs. The enrolled patients were assigned to two groups based on whether they received afatinib or dacomitinib.
RESULTS
A total of 101 patients were enrolled in the study (70 to afatinib and 31 to dacomitinib). The partial response rates (PR) for first-line treatment with afatinib and dacomitinib were 85.7 and 80.6% (p = 0.522). The median progression-free survival (PFS) (18.9 vs. 16.3 months, p = 0.975) and time to treatment failure (TTF) (22.7 vs. 15.9 months, p = 0.324) in patients with afatinib and dacomitinib treatment were similar. There was no significant difference observed in the median PFS (16.1 vs. 18.9 months, p = 0.361) and TTF (32.5 vs. 19.6 months, p = 0.182) between patients receiving the standard dose and those receiving the reduced dose. In terms of side effects, the incidence of diarrhea was higher in the afatinib group (75.8% vs. 35.5%, p < 0.001), while the incidence of paronychia was higher in the dacomitinib group (58.1% vs. 31.4%, p = 0.004). The PFS (17.6 vs. 24.9 months, p = 0.663) and TTF (21.3 vs. 25.1 months, p = 0.152) were similar between patients younger than 75 years and those older than 75 years.
CONCLUSION
This study showed that afatinib and dacomitinib had similar effectiveness and safety profiles. However, they have slightly different side effects. Afatinib and dacomitinib can be safely administered to patients across different age groups with appropriate dose reductions.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Afatinib; Lung Neoplasms; Retrospective Studies; Protein Kinase Inhibitors; Treatment Outcome; ErbB Receptors; Mutation; Quinazolinones
PubMed: 38373960
DOI: 10.1186/s12885-024-11956-w -
Clinical & Experimental Metastasis Apr 2024Human epidermal growth factor 2 (HER2)-positive breast cancer with lung metastases resistant to targeted agents is a common therapeutic challenge. Absence of preclinical... (Comparative Study)
Comparative Study
Human epidermal growth factor 2 (HER2)-positive breast cancer with lung metastases resistant to targeted agents is a common therapeutic challenge. Absence of preclinical lung metastasis models that are resistant to multiple anti-HER2 targeted drugs hampers the development of novel therapies. We established a novel HER2-positive breast cancer cell line (L-JIMT-1) with a high propensity to form lung metastases from the parenteral JIMT-1 cell line by injecting JIMT-1 cells into immunodeficient SCID mice. Lung metastases developed in all mice injected with L-JIMT-1 cells, and more rapidly and in greater numbers compared with the parental JIMT-1 cells. L-JIMT-1 cells expressed more epidermal growth factor receptor and HER2 than JIMT-1 cells. L-JIMT-1 cells were resistant to all five tyrosine kinase inhibitors tested in vitro (afatinib, erlotinib, lapatinib, sapitinib, and tucatinib). When we compared JIMT-1 and L-JIMT-1 sensitivity to three HER2-targeting antibody-drug conjugates (ADCs) trastuzumab emtansine (T-DM1), trastuzumab deruxtecan (T-DXd), and disitamab vedotin (DV) in vitro, JIMT-1 cells were resistant T-DXd, partially sensitive to T-DM1, and sensitive to DV, while L-JIMT-1 cells were resistant to both T-DM1 and T-DXd, but moderately sensitive to DV. In a mouse model, all three ADCs inhibited the growth of L-JIMT-1 lung metastases compared to a vehicle, but DV and T-DXd more strongly than T-DM1, and DV treatment led to the smallest tumor burden. The L-JIMT breast cancer lung metastasis model developed may be useful in the evaluation of anti-cancer agents for multiresistant HER2-positive advanced breast cancer.
Topics: Animals; Female; Humans; Mice; Ado-Trastuzumab Emtansine; Antibodies, Monoclonal; Antineoplastic Agents; Breast Neoplasms; Camptothecin; Immunoconjugates; Lung Neoplasms; Mice, SCID; Oligopeptides; Receptor, ErbB-2; Trastuzumab
PubMed: 38367127
DOI: 10.1007/s10585-024-10278-2 -
Frontiers in Oncology 2024Lung cancer treatment has transitioned fully into the era of immunotherapy, yielding substantial improvements in survival rate for patients with advanced non-small cell...
Lung cancer treatment has transitioned fully into the era of immunotherapy, yielding substantial improvements in survival rate for patients with advanced non-small cell lung cancer (NSCLC). In this report, we present a case featuring a rare epidermal growth factor receptor () mutation accompanied by high programmed death-ligand 1 () expression, demonstrating remarkable therapeutic efficacy through a combination of immunotherapy and chemotherapy. A 77-year-old male with no family history of cancer suffered from upper abdominal pain for more than half months in August 2020 and was diagnosed with stage IV (cT3N3M1c) lung squamous cell carcinoma (LUSC) harboring both a rare p.G719C mutation and high expression of (tumor proportion score [TPS] = 90%). Treatment with the second-generation targeted therapy drug Afatinib was initiated on September 25, 2020. However, resistance ensued after 1.5 months of treatment. On November 17, 2020, immunotherapy was combined with chemotherapy (Sintilimab + Albumin-bound paclitaxel + Cisplatin), and a CT scan conducted three months later revealed significant tumor regression with a favorable therapeutic effect. Subsequently, the patient received one year of maintenance therapy with Sintilimab, with follow-up CT scans demonstrating subtle tumor shrinkage (stable disease). This case provides evidence for the feasibility and efficacy of immunotherapy combined with chemotherapy in the treatment of -mutated and highly expressed LUSC.
PubMed: 38357203
DOI: 10.3389/fonc.2024.1283008