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Briefings in Bioinformatics Mar 2024Lung adenocarcinoma (LUAD) is the most common histologic subtype of lung cancer. Early-stage patients have a 30-50% probability of metastatic recurrence after surgical...
Lung adenocarcinoma (LUAD) is the most common histologic subtype of lung cancer. Early-stage patients have a 30-50% probability of metastatic recurrence after surgical treatment. Here, we propose a new computational framework, Interpretable Biological Pathway Graph Neural Networks (IBPGNET), based on pathway hierarchy relationships to predict LUAD recurrence and explore the internal regulatory mechanisms of LUAD. IBPGNET can integrate different omics data efficiently and provide global interpretability. In addition, our experimental results show that IBPGNET outperforms other classification methods in 5-fold cross-validation. IBPGNET identified PSMC1 and PSMD11 as genes associated with LUAD recurrence, and their expression levels were significantly higher in LUAD cells than in normal cells. The knockdown of PSMC1 and PSMD11 in LUAD cells increased their sensitivity to afatinib and decreased cell migration, invasion and proliferation. In addition, the cells showed significantly lower EGFR expression, indicating that PSMC1 and PSMD11 may mediate therapeutic sensitivity through EGFR expression.
Topics: Humans; Adenocarcinoma of Lung; Lung Neoplasms; Cell Line, Tumor; Biomarkers, Tumor; Gene Expression Regulation, Neoplastic; ErbB Receptors; Cell Proliferation
PubMed: 38557672
DOI: 10.1093/bib/bbae080 -
Comprehensive mutational scanning of EGFR reveals TKI sensitivities of extracellular domain mutants.Nature Communications Mar 2024The epidermal growth factor receptor, EGFR, is frequently activated in lung cancer and glioblastoma by genomic alterations including missense mutations. The different...
The epidermal growth factor receptor, EGFR, is frequently activated in lung cancer and glioblastoma by genomic alterations including missense mutations. The different mutation spectra in these diseases are reflected in divergent responses to EGFR inhibition: significant patient benefit in lung cancer, but limited in glioblastoma. Here, we report a comprehensive mutational analysis of EGFR function. We perform saturation mutagenesis of EGFR and assess function of ~22,500 variants in a human EGFR-dependent lung cancer cell line. This approach reveals enrichment of erlotinib-insensitive variants of known and unknown significance in the dimerization, transmembrane, and kinase domains. Multiple EGFR extracellular domain variants, not associated with approved targeted therapies, are sensitive to afatinib and dacomitinib in vitro. Two glioblastoma patients with somatic EGFR G598V dimerization domain mutations show responses to dacomitinib treatment followed by within-pathway resistance mutation in one case. In summary, this comprehensive screen expands the landscape of functional EGFR variants and suggests broader clinical investigation of EGFR inhibition for cancers harboring extracellular domain mutations.
Topics: Humans; Glioblastoma; Protein Kinase Inhibitors; ErbB Receptors; Lung Neoplasms; Mutation
PubMed: 38548752
DOI: 10.1038/s41467-024-45594-4 -
World Journal of Oncology Apr 2024Of various human epidermal growth factor receptor (HER) inhibitors, only the anti-HER2 monoclonal antibody (mAb) Herceptin/trastuzumab and the antibody-drug conjugate...
BACKGROUND
Of various human epidermal growth factor receptor (HER) inhibitors, only the anti-HER2 monoclonal antibody (mAb) Herceptin/trastuzumab and the antibody-drug conjugate trastuzumab deruxtecan (T-Dxd) has been approved for the treatment of patients with stomach cancer. However, the duration of response may be short in many patients, with tumor heterogeneity being one contributing factor.
METHODS
We investigated the effect of various types of targeted agents on growth and migration of a panel of human stomach cancer cells (HSCCLs) and the impact of cell proliferation rate on the anti-tumor activities of these agents. We also investigated the association between the cell surface expression of the HER family members, hepatocyte growth factor receptor (c-Met), anaplastic lymphoma kinase (ALK)7 and cancer stem cell markers CD44 and CD133, and the response to the targeted agents.
RESULTS
Of the 18 agents examined, the cyclin dependent kinase (CDK) 1/2/5/9 inhibitor dinaciclib was the most effective and inhibited the growth of all human HSCCLs at 50% inhibitory concentration (IC) values between 9 nM to 23 nM. Of various HER inhibitors, the irreversible pan-HER family inhibitors (e.g., afatinib) were more effective than the reversible dual epidermal growth factor receptor (EGFR)/HER2 tyrosine kinase inhibitor (TKI) lapatinib and the EGFR-specific TKI erlotinib in inhibiting the growth of HSCCLs. Of agents targeting different downstream cell signaling molecules, dasatinib targeting Ab1/Src/C-Kit, trametinib targeting MERK1/2 and miransertib targeting AKT1/2/3 inhibited growth of majority of HSCCLs, with the IC values ranging from 2 nM to 7 µM. Many of these agents were more effective in inhibiting the growth of HSCCLs when they were proliferating at a slower rate. Treatment with neratinib, afatinib, dinaciclib, dasatinib, stattic, miransertib and paclitaxel significantly inhibited migration of stomach cancer cells. Interestingly, treatment with a combination of afatinib and dasatinib or afatinib and miransertib resulted in synergistic and additive growth inhibition of stomach cancer cells.
CONCLUSIONS
These results suggest that treatment with a combination of these agents may be of therapeutic value in stomach cancer and warrants further investigations.
PubMed: 38545471
DOI: 10.14740/wjon1769 -
ESMO Open Apr 2024Over the past two decades, our group has conducted five multicenter trials focusing on first-line systemic therapy for patients with advanced pancreatic cancer. The...
Changes over time in the course of advanced pancreatic cancer treatment with systemic chemotherapy: a pooled analysis of five clinical trials from two decades of the German AIO study group.
BACKGROUND
Over the past two decades, our group has conducted five multicenter trials focusing on first-line systemic therapy for patients with advanced pancreatic cancer. The current pooled analysis was designed to evaluate prognosis over time and the impact of clinical characteristics on survival.
PATIENTS AND METHODS
Individual patient data were derived from five prospective, controlled, multicenter trials conducted by the 'Arbeitsgemeinschaft Internistische Onkologie' (AIO): 'Gem/Cis', 'Ro96', 'RC57', 'ACCEPT' and 'RASH', which recruited patients between December 1997 and January 2017.
RESULTS
Overall, 912 patients were included. The median overall survival (OS) for all assessable patients was 7.1 months. OS significantly improved over time, with a median OS of 8.6 months for patients treated from 2012 to 2017 compared with 7.0 months from 1997 to 2006 [hazard ratio (HR) 1.06; P < 0.004]. Eastern Cooperative Oncology Group performance status (HR 1.48; P < 0.001), use of second-line treatment (HR 1.51; P < 0.001), and Union for International Cancer Control (UICC) stage (III versus IV) (HR 1.34, P = 0.002) had a significant impact on OS. By contrast, no influence of age and gender on OS was detectable. Comparing combination therapy with single-agent chemotherapy did not demonstrate a survival benefit, nor did regimens containing epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) such as afatinib or erlotinib, compared with chemotherapy-only arms. Patients with early-onset pancreatic cancer (age at study entry of ≤50 years, n = 102) had a similar OS compared with those >50 years (7.1 versus 7.0 months; HR 1.13; P = 0.273). The use of a platinum-containing regimen was not associated with better outcomes in patients with early-onset pancreatic cancer.
CONCLUSIONS
Within this selected group of patients treated within prospective clinical trials, survival has shown improvement over two decades. This effect is likely attributable to the availability of more effective combination therapies and treatment lines, rather than to any specific regimen, such as those containing EGFR-TKIs. In addition, concerning age and sex subgroups, the dataset did not provide evidence for distinct clinical behavior.
Topics: Humans; Pancreatic Neoplasms; Male; Female; Middle Aged; Aged; Germany; Antineoplastic Combined Chemotherapy Protocols; Adult; Prospective Studies; Aged, 80 and over; Prognosis
PubMed: 38503144
DOI: 10.1016/j.esmoop.2024.102944 -
ERJ Open Research Mar 2024Afatinib, an irreversible ErbB family inhibitor, is widely used as first-line treatment in advanced lung adenocarcinoma patients harbouring mutant epidermal growth...
BACKGROUND
Afatinib, an irreversible ErbB family inhibitor, is widely used as first-line treatment in advanced lung adenocarcinoma patients harbouring mutant epidermal growth factor receptor (EGFR). With the advancements in next-generation sequencing (NGS), comprehensive research into the clinical impact of co-occurring genetic mutations and the molecular mechanisms of acquired resistance is required for afatinib users.
MATERIALS
From January 2010 to December 2019, we enrolled patients with advanced lung adenocarcinoma with mutations using afatinib as first-line treatment, and we retrospectively collected pre- and post-afatinib treatment specimens from these patients for NGS testing.
RESULTS
Of the 362 enrolled patients, 73 samples (68.9%) from 56 patients successfully returned complete NGS reports. In pre-afatinib treatment specimens, the most frequent co-occurring alterations were , , , , and ; however, they were not related to progression-free survival. Small cell lung cancer transformation, p.T790M, amplification of , , , , cell cycle-regulated genes and , and alterations were identified as acquired resistance mechanisms. p.T790M (p=0.0304) and alterations (p=0.0311) in post-afatinib specimens were significantly associated with longer overall survival, while amplification was significantly associated with poor overall survival (p=0.0324). The co-occurrence of alterations was significantly associated with shorter overall survival (p=0.0298).
CONCLUSIONS
Our results show that the frequent co-occurring alterations in advanced -mutated lung adenocarcinoma did not influence the effectiveness of afatinib. p.T790M is not only the major resistance mechanism to afatinib but also related to favourable survival outcomes. amplification and mutations were associated with poorer overall survival.
PubMed: 38500795
DOI: 10.1183/23120541.00676-2023 -
Journal of Thoracic Oncology : Official... Mar 2024Uncommon EGFR mutations represent a rare subgroup of NSCLC. Data on the efficacy of different generations of tyrosine kinase inhibitors (TKIs) in these rare mutations... (Review)
Review
Uncommon EGFR mutations represent a rare subgroup of NSCLC. Data on the efficacy of different generations of tyrosine kinase inhibitors (TKIs) in these rare mutations are scattered and limited to mostly retrospective small cohorts because these patients were usually excluded from clinical trials. This was a systematic review on the efficacy of TKIs in patients harboring uncommon EGFR mutations, defined as mutations other than exon 20 insertions mutations or T790M. Response rates (RRs) for different generations of TKIs were determined for individual uncommon mutations, compound mutations, and according to classical-like and P-loop alpha helix compressing mutations classes. This study was conducted in accordance with the 2009 Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. A total of 1836 patients from 38 studies were included in the final analysis. Most available data (92.6%) were from patients treated with first- or second-generation TKIs. G719X, S768I, E709X, L747X, and E709-T710delinsD showed RRs ranging from 47.8% to 72.3% to second-generation TKIs, generally higher than for first- or third-generation TKIs. L861Q mutation exhibited 75% (95% confidence interval [CI]: 56.6%-88.5%) RRs to third-generation TKIs. Compound mutations with G719X, E709X, or S768I consistently showed RRs above 50% to second- and third-generation TKIs, although fewer data were available for third generations. For classical-like mutations, RRs were 35.4% (95% CI: 27.2%-44.2%), 51.9% (95% CI: 44.4%-59.3%), and 67.9% (95% CI: 47.6%-84.1%) to first-, second-, and third-generation TKIs, whereas for P-loop alpha helix compressing mutations classes mutations, RRs were 37.2% (95% CI: 32.4%-42.1%), 59.6% (95% CI: 54.8%-64.3%), and 46.3% (95% CI: 32.6%-60.4%), respectively. This systematic review supports the use of second-generation TKI afatinib for G719X, S768I, E709X, and L747X mutations and for compound uncommon mutations. For other uncommon mutations such as L861Q, third-generation TKI, such as osimertinib, could also be considered, given its activity and toxicity profile.
PubMed: 38499147
DOI: 10.1016/j.jtho.2024.03.016 -
Oncotarget Mar 2024Here, I suggest that while first-line osimertinib extends median progression-free survival (PFS) in EGFR-mutant lung cancer compared to first-generation TKIs, it reduces...
Here, I suggest that while first-line osimertinib extends median progression-free survival (PFS) in EGFR-mutant lung cancer compared to first-generation TKIs, it reduces individual PFS in 15-20% of patients compared to first-generation TKIs. Since detecting a single resistant cell before treatment is usually impossible, osimertinib must be used in all patients as a first-line treatment, raising median PFS overall but harming some. The simplest remedy is a preemptive combination (PC) of osimertinib and gefitinib. A comprehensive PC (osimertinib, afatinib/gefitinib, and capmatinib) could dramatically increase PFS for 80% of patients compared to osimertinib alone, without harming anyone. This article also explores PCs for MET-driven lung cancer.
Topics: Humans; Gefitinib; Acrylamides; Afatinib; Lung Neoplasms; Aniline Compounds; Indoles; Pyrimidines
PubMed: 38497774
DOI: 10.18632/oncotarget.28569 -
Translational Lung Cancer Research Feb 2024Afatinib can be started at a dose lower than the recommended starting dose of 40 mg/day for the treatment of epidermal growth factor receptor ()-mutant non-small cell...
BACKGROUND
Afatinib can be started at a dose lower than the recommended starting dose of 40 mg/day for the treatment of epidermal growth factor receptor ()-mutant non-small cell lung cancer (NSCLC), however treatment outcomes in real-world clinical practice remains unclear.
METHODS
This retrospective study of patients with NSCLC from 18 major hospitals (public, private or university teaching hospitals) enrolled in Malaysia's National Cardiovascular and Thoracic Surgical Database (NCTSD) assessed the efficacy of lower doses of afatinib on treatment outcomes in a real-world clinical practice. Data on clinical characteristics, afatinib dosing, and treatment outcomes for patients included in NCTSD from 1 January 2015 to 31 December 2020 were analyzed.
RESULTS
Of the 133 patients studied, 94.7% had adenocarcinoma. Majority of the patients (60.9%) had exon 19 deletion and 23.3% had exon 21 L858R point mutation. The mean age of patients was 64.1 years and majority (83.5%) had Eastern Cooperative Oncology Group performance status of 2-4 at diagnosis. The most common afatinib starting doses were 40 mg (37.6%), 30 mg (29.3%), and 20 mg (26.3%) once daily (OD), respectively. A quarter of patients had dose reduction (23.3%) due to side effects or cost constraints. Majority of the patients had partial response to afatinib (63.2%) whilst 2.3% had complete response. Interestingly, the objective response rate was significantly higher (72.3%) with afatinib OD doses of less than 40 mg compared to 40 mg (54.0%) (P=0.032). Patients on lower doses of afatinib were two times more likely to achieve an objective response [odds ratio =2.64; 95% confidence interval (CI): 1.20-5.83; P=0.016]. These patients had a numerically but not statistically longer median time to treatment failure (TTF). Median TTF (95% CI) for the overall cohort was 12.4 (10.02-14.78) months. Median overall survival (95% CI) was 21.30 (15.86-26.75) months.
CONCLUSIONS
Lower afatinib doses (<40 mg OD) could be equally effective as standard dose in patients with -mutant advanced NSCLC and may be more suited to Asian patients, minimizing side effects that may occur at higher dosages of afatinib leading to dose interruptions and affecting treatment outcomes.
PubMed: 38496703
DOI: 10.21037/tlcr-23-691 -
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