Background: Human epidermal growth factor 2 (HER2/ERBB2) is frequently amplified/mutated in cancer. The tyrosine kinase inhibitors (TKIs) lapatinib, neratinib, and tucatinib are FDA-approved for the treatment of HER2-positive breast cancer. Direct comparisons of the preclinical efficacy of the TKIs have been limited to small-scale studies. Novel biomarkers are required to define beneficial patient populations.
Methods: In this study, the anti-proliferative effects of the three TKIs were directly compared using a 115 cancer cell line panel. Novel TKI response/resistance markers were identified through cross-analysis of drug response profiles with mutation, gene copy number and expression data.
Results: All three TKIs were effective against HER2-amplified breast cancer models; neratinib showing the most potent activity, followed by tucatinib then lapatinib. Neratinib displayed the greatest activity in HER2-mutant and EGFR-mutant cells. High expression of HER2, VTCN1, CDK12, and RAC1 correlated with response to all three TKIs. DNA damage repair genes were associated with TKI resistance. BRCA2 mutations were correlated with neratinib and tucatinib response, and high expression of ATM, BRCA2, and BRCA1 were associated with neratinib resistance.
Conclusions: Neratinib was the most effective HER2-targeted TKI against HER2-amplified, -mutant, and EGFR-mutant cell lines. This analysis revealed novel resistance mechanisms that may be exploited using combinatorial strategies.
Download full-text PDF |
Source |
---|---|
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8007737 | PMC |
http://dx.doi.org/10.1038/s41416-020-01257-x | DOI Listing |
World J Urol
January 2025
Medical Oncology Department, Institut de Cancérologie Strasbourg Europe, Strasbourg, France.
Purpose: Surgery remains the cornerstone of localized renal cell carcinoma (RCC) care. Pembrolizumab has recently been recommended as a standard of care for RCC patients who are at high risk of recurrence. Data regarding the efficacy of ICIs either alone or in combination with ICIs or VEGF TKIs for VTT shrinkage are scarce.
View Article and Find Full Text PDFMed Int (Lond)
December 2024
Department of Clinical and Experimental Medicine, Endocrine Unit 2, University of Pisa, I-56122 Pisa, Italy.
The limitations of two-dimensional (2D) models in cancer research have hindered progress in fully understanding the complexities of drug resistance and therapeutic failures. However, three-dimensional (3D) models provide a more accurate representation of environments, capturing critical cellular interactions and dynamics that are essential in evaluating the efficacy and toxicity of tyrosine kinase inhibitors (TKIs). These advanced models enable researchers to explore drug resistance mechanisms with greater precision, optimizing treatment strategies and improving the predictive accuracy of clinical outcomes.
View Article and Find Full Text PDFRadiat Oncol
January 2025
Department of Oncology, The Second Affiliated Hospital of Chongqing Medical University, 76 Linjiang Road, Yuzhong District, Chongqing, 400010, China.
Background: Patients with non-small cell lung cancer (NSCLC) are prone to developing brain metastases (BMs), particularly those with epidermal growth factor receptor (EGFR) mutations. In clinical practice, treatment-naïve EGFR-mutant NSCLC patients with asymptomatic BMs tend to choose EGFR-tyrosine kinase inhibitors (TKIs) as first-line therapy and defer intracranial radiotherapy (RT). However, the effectiveness of upfront intracranial RT remains unclear.
View Article and Find Full Text PDFBiomedicines
December 2024
Oncological Endocrinology Unit, IRCCS Regina Elena National Cancer Institute, Via Elio Chianesi 53, 00144 Rome, Italy.
: The current possible treatments of advanced medullary carcinoma (MTC) include different drugs belonging to the class of tyrosine kinase inhibitors (TKIs): vandetanib, cabozantinb, and selpercatinib. Although the effects of these TKIs have been well described in clinical trials, the real-practice evidence of the effectiveness and safety of these treatment is scant. This real-world case series aims to describe a niche of patients with advanced MTC treated with more than one TKI by focusing on treatment responses and any reported adverse events (AEs) and to provide additional insight on the individualized approach to the management of metastatic MTC.
View Article and Find Full Text PDFGenes (Basel)
December 2024
Department of Pulmonology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Yokohama 236-0004, Japan.
: This research aims to investigate the mechanisms of resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in non-small-cell lung cancer (NSCLC), particularly focusing on the role of the epithelial-mesenchymal transition (EMT) within the tumor microenvironment (TME). : We employed an in vitro three-dimensional organoid model that mirrors the physiology of human lung cancer. These organoids consist of lung cancer cells harboring specific mutations, human mesenchymal stem cells, and human umbilical vein endothelial cells.
View Article and Find Full Text PDFEnter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!