@conference{
author = "Lupšić, Ema and Dinić, Jelena and Dragoj, Miodrag and Jovanović Stojanov, Sofija and Stepanović, Ana and Pajović, Milica and Mohr, Thomas and Glumac, Sofija and Marić, Dragana and Ercegovac, Maja and Podolski-Renić, Ana and Pešić, Milica",
year = "2024",
abstract = "Lung cancer remains the leading cause of cancer death globally, with non-small cell lung cancer (NSCLC) accounting for the majority of cases. Despite advances in diagnosis and treatment modalities, NSCLC remains a major challenge in clinical oncology. Recently, a functional diagnostics approach has been proposed, integrating the treatment response of patient-derived cancer cells with the patient’s genetic profile to recommend the optimal therapy for NSCLC. The aim of our study was to evaluate the response of 17 patient-derived NSCLC cultures to 10 commonly prescribed tyrosine kinase inhibitors (TKIs) and correlate these responses with patient mutational profiles.
Primary patient-derived cultures, established from the NSCLC resections, with a mixed population of cancer and non-cancer cells were treated with 10 TKIs (afatinib, alectinib, ceritinib, crizotinib, dabrafenib, erlotinib, gefitinib, nintedanib, osimertinib and trametinib). Immunofluorescence assay enabling discrimination of epithelial cancer cells positive to a cocktail of antibodies against cytokeratin 8/18 vs. negative mesenchymal non-cancer cells was conducted using high-content imager ImageXpress Pico (Molecular Devices) with CellReporterXpress 2.9 software. As a part of a functional diagnostic approach whole-exome sequencing (WES) was performed to provide a comprehensive molecular profile of the patient's tumor.
NSCLC cultures responded differently to TKIs, with erlotinib showing good efficacy regardless of mutation burden or EGFR status. In addition, erlotinib exclusively inhibited the growth of cancer cells in NSCLC cultures while sparing stromal cells (CK8/18- cells). Other TKIs showed limited efficacy, highlighting the variability of response in NSCLC. Genetic alterations in signaling pathways associated with drug resistance and sensitivity, likely contributed to the variable responses to TKIs. Notably, TP53 was the most frequently mutated gene, with alterations detected in 65% of patients. In addition, the results from the KEGG pathways analysis showed that the variants were highly clustered in several signaling pathways such as PI3K-Akt pathway, EGFR tyrosine kinase inhibitor resistance and ErbB pathway.
Our results suggest that in addition to mutational status, performing functional sensitivity screening is critical for identifying appropriate treatment strategies with TKIs. These results underscore the importance of considering drug sensitivity, off-target effects, and patient-specific genetic profiles to optimize treatment strategies for NSCLC.",
publisher = "EMBO press",
journal = "Abstract book: Molecular mechanisms in signal transduction and cancer: EMBO-FEBS Lecture course; 2024 Aug 18-26; Spetses, Greece",
title = "Functional diagnostics in non-small cell lung carcinoma - the potential for personalized approach",
url = "https://hdl.handle.net/21.15107/rcub_ibiss_7032"
}
