Brief Report: Combination of Osimertinib and Dacomitinib to Mitigate Primary and Acquired Resistance inEGFR-Mutant Lung Adenocarcinomas

Clinical Cancer Research, Journal Year: 2023, Volume and Issue: 29(8), P. 1423 - 1428

Published: Feb. 2, 2023

Abstract Purpose: Primary and acquired resistance to osimertinib remain significant challenges for patients with EGFR-mutant lung cancers. Acquired EGFR alterations such as T790M or C797S mediate tyrosine kinase inhibitors (TKI) combination therapy dual TKIs may prevent reverse on-target resistance. Patients Methods: We conducted two prospective, phase I/II trials assessing dacomitinib address in the primary settings. In initial study, received therapy. trial, without was administered cancers disease progression on alone evidence of an second-site mutation. Results: Cutaneous toxicities occurred 93% (any grade) diarrhea 72% combination. As therapy, overall response 73% [95% confidence interval (CI), 50%–88%]. No secondary were observed any at progression. setting, 14% (95% CI, 1%–58%). Conclusions: no inhibition up-front treatment, but this regimen associated greater toxicity. The not effective reversing after development a alteration. Our study highlights need develop better strategies

Language: Английский

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Chemotherapy outcomes in EGFR‐TKI resistant patients with common and uncommon EGFR mutation: An exploratory retrospective cohort study

Thoracic Cancer, Journal Year: 2023, Volume and Issue: 14(19), P. 1857 - 1864

Published: May 15, 2023

Abstract Background Some prospective studies have shown that second‐generation tyrosine kinase inhibitors (TKIs) provide better control in patients with non‐small cell lung cancer (NSCLC) uncommon epidermal growth factor receptor ( EGFR ) mutations. However, comparing second‐line chemotherapy efficacy between NSCLC common and mutations remain rare. This retrospective study compared treatment outcomes these patients. Methods Patients ‐mutated advanced‐stage who received first‐line EGFR‐TKIs a tertiary referral center were retrospectively reviewed January 2010 August 2022. negative T790M test at disease progression enrolled. We progression‐free (PFS) overall (OS) survival advanced using Kaplan–Meier log‐rank tests. Results In total, 209 (54.8%) had mutation chemotherapy, of which 192 (91.8%) (exon 19 deletion or exon 21 L858R substitution), 17 (8.2%) an mutation. significantly longer PFS than those (4.57 vs. 2.57 months, p = 0.031). A Cox proportional hazard regression analysis controlling for potential confounding factors indicated was independent prognostic PFS. Conclusion suggests poorer responses shorter The development new strategies remains unmet need.

Language: Английский

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Optimal First-Line Treatment for EGFR-Mutated NSCLC: A Comparative Analysis of Osimertinib and Second-Generation EGFR-TKIs

Research Square (Research Square), Journal Year: 2024, Volume and Issue: unknown

Published: Jan. 22, 2024

Abstract Background Osimertinib is an irreversible third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI). It the preferred first-line treatment for EGFR-mutated non-small cell lung cancer (NSCLC) compared to first-generation EGFR-TKIs. However, limited research has its clinical effectiveness with second-generation (2 nd G) Materials and Methods This study recruited patients diagnosed stage IIIb-IV NSCLC who received either 2 G EGFR-TKIs (afatinib dacomitinib) or osimertinib between April 2020 2023. Results The final analysis included 168 patients, of whom 113 55 osimertinib. median progression-free survival (PFS) did not differ significantly (del 19: 17.6 months; L858R: 20.0 months vs. 28.3 months, p = 0.081). In EGFR exon 19 deletion, conferred a longer PFS (28.3 0.118) time failure (30.2 22.7 0.722) than differences were statistically significant. deletion central nervous system metastasis, those treated (14.3 months) 2nd (17.6 0.881). Multivariate regression revealed that was only independent negative predictor PFS. patterns in second line also differed groups ( 0.008). Conclusions found comparable as advanced NSCLC, identified whether different second-line treatments affect overall should be examined.

Language: Английский

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Exploring acenocoumarol and silodosin as allosteric EGFR inhibitors for the treatment of non-small cell lung cancer

F1000Research, Journal Year: 2024, Volume and Issue: 13, P. 1398 - 1398

Published: Nov. 21, 2024

Background Non-small-cell lung cancer (NSCLC) is a highly morbid disease. Chemotherapy for NSCLC lacks specificity and efficacy mainly because of drug resistance. The current study aimed to explore computational tools target allosteric epidermal growth factor receptor (EGFR) sites screen the top molecules in vitro vivo xenograft models. Methods Molecular docking, virtual screening, molecular dynamic studies revealed that acenocoumarol silodosin are two EGFR inhibitors. They were further tested cytotoxicity, apoptosis, cell cycle, gene expression by qPCR, western blotting, A549 anti-proliferative activity, tumor regression analysis. Results Acenocoumarol exhibited cytotoxicity in IMR-90 cells at concentrations below 50 80 μM, respectively. induced S-phase G2/M-phase arrest cycle Both drugs showed early apoptosis their IC50 doses (acenocoumarol μM 25 μM). KRAS (Kirsten rat sarcoma viral oncogene homolog) ERK2 (extracellular signal-regulated kinase 2) regulation was confirmed using qPCR. activities quantified blot In study, size, body weight, organ weight significantly attenuated test compared with standard cisplatin. Immunoblotting results A549-xenograft tissue indicated downregulation ERK2. Furthermore, have upregulated caspase-3 expression. Conclusion downregulate both line Xenograft model. associated inhibition. Hence, can be explored repurposing human trials.

Language: Английский

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