Transcriptomic heterogeneity of EGFR-mutant non-small cell lung cancer evolution towards small cell lung cancer
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE259387 | GEO | 2024/07/30
REPOSITORIES: GEO
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Project description:The study was designed to identify the molecular changes that occur in EGFR mutant NSCLCs that become resistant to TKI by transforming to SCLC. Tyrosine kinase inhibitors (TKIs) are effective treatments for non-small cell lung cancers (NSCLCs) with epidermal growth factor receptor (EGFR) mutations. However, they do not lead to cures, and, on average, relapse occurs after one year of continuous treatment. In a subset of patients, a fundamental histological transformation from NSCLC to small cell lung cancer (SCLC) is observed in the resistant cancers, but the molecular changes associated with this transformation remain unknown. Analysis of a cohort of tumor samples and cell lines derived from resistant EGFR mutant patients with SCLC transformation revealed that RB is lost in 100% of these cases, but rarely in those that remain NSCLC. Global changes in gene expression, including increased neuroendocrine marker expression and absence of EGFR expression, are observed in cancers that transformed to SCLC. Consistent with their genetic and epigenetic similarities to classical SCLC, cell lines derived from resistant EGFR mutant SCLC biopsies are substantially more sensitive to ABT-263 treatment compared to those derived from resistant EGFR mutant NSCLCs. Together, these findings suggest that despite developing initially as EGFR mutant adenocarcinomas, this subset of resistant cancers ultimately take on many of the molecular and phenotypic characteristics of classical SCLC. Overall, we completed array CGH analysis on 4 tumor specimens from EGFR mutant, TKI-resistant patients. Three of these samples had transformed to SCLC and one remained NSCLC.
2015-01-30 | E-GEOD-64765 | biostudies-arrayexpress
Project description:The study was designed to identify the molecular changes that occur in EGFR mutant NSCLCs that become resistant to TKI by transforming to SCLC. Tyrosine kinase inhibitors (TKIs) are effective treatments for non-small cell lung cancers (NSCLCs) with epidermal growth factor receptor (EGFR) mutations. However, they do not lead to cures, and, on average, relapse occurs after one year of continuous treatment. In a subset of patients, a fundamental histological transformation from NSCLC to small cell lung cancer (SCLC) is observed in the resistant cancers, but the molecular changes associated with this transformation remain unknown. Analysis of a cohort of tumor samples and cell lines derived from resistant EGFR mutant patients with SCLC transformation revealed that RB is lost in 100% of these cases, but rarely in those that remain NSCLC. Global changes in gene expression, including increased neuroendocrine marker expression and absence of EGFR expression, are observed in cancers that transformed to SCLC. Consistent with their genetic and epigenetic similarities to classical SCLC, cell lines derived from resistant EGFR mutant SCLC biopsies are substantially more sensitive to ABT-263 treatment compared to those derived from resistant EGFR mutant NSCLCs. Together, these findings suggest that despite developing initially as EGFR mutant adenocarcinomas, this subset of resistant cancers ultimately take on many of the molecular and phenotypic characteristics of classical SCLC.
2015-01-30 | GSE64765 | GEO
Project description:The study was designed to identify the molecular changes that occur in EGFR mutant NSCLCs that become resistant to TKI by transforming to SCLC. Tyrosine kinase inhibitors (TKIs) are effective treatments for non-small cell lung cancers (NSCLCs) with epidermal growth factor receptor (EGFR) mutations. However, they do not lead to cures, and, on average, relapse occurs after one year of continuous treatment. In a subset of patients, a fundamental histological transformation from NSCLC to small cell lung cancer (SCLC) is observed in the resistant cancers, but the molecular changes associated with this transformation remain unknown. Analysis of a cohort of tumor samples and cell lines derived from resistant EGFR mutant patients with SCLC transformation revealed that RB is lost in 100% of these cases, but rarely in those that remain NSCLC. Global changes in gene expression, including increased neuroendocrine marker expression and absence of EGFR expression, are observed in cancers that transformed to SCLC. Consistent with their genetic and epigenetic similarities to classical SCLC, cell lines derived from resistant EGFR mutant SCLC biopsies are substantially more sensitive to ABT-263 treatment compared to those derived from resistant EGFR mutant NSCLCs. Together, these findings suggest that despite developing initially as EGFR mutant adenocarcinomas, this subset of resistant cancers ultimately take on many of the molecular and phenotypic characteristics of classical SCLC.
2015-01-30 | GSE64322 | GEO
Project description:The study was designed to identify the molecular changes that occur in EGFR mutant NSCLCs that become resistant to TKI by transforming to SCLC. Tyrosine kinase inhibitors (TKIs) are effective treatments for non-small cell lung cancers (NSCLCs) with epidermal growth factor receptor (EGFR) mutations. However, they do not lead to cures, and, on average, relapse occurs after one year of continuous treatment. In a subset of patients, a fundamental histological transformation from NSCLC to small cell lung cancer (SCLC) is observed in the resistant cancers, but the molecular changes associated with this transformation remain unknown. Analysis of a cohort of tumor samples and cell lines derived from resistant EGFR mutant patients with SCLC transformation revealed that RB is lost in 100% of these cases, but rarely in those that remain NSCLC. Global changes in gene expression, including increased neuroendocrine marker expression and absence of EGFR expression, are observed in cancers that transformed to SCLC. Consistent with their genetic and epigenetic similarities to classical SCLC, cell lines derived from resistant EGFR mutant SCLC biopsies are substantially more sensitive to ABT-263 treatment compared to those derived from resistant EGFR mutant NSCLCs. Together, these findings suggest that despite developing initially as EGFR mutant adenocarcinomas, this subset of resistant cancers ultimately take on many of the molecular and phenotypic characteristics of classical SCLC. The patient-derived cell line models MGH119, MGH121, MGH125, MGH126, MGH131-1, MGH131-2, MGH134 and MGH156 were developed on collagen coated plates in ACL4 medium and transferred to RPMI. MGH157 was developed initially in RPMI. The cell line MGH141 was derived using the feeder system with irradiated fibroblasts (5000 rad) from normal patient tissue. When a tumor cell majority was observed it was passaged off of the feeder layer and later transferred to RPMI medium for experiments. The development of a model was considered complete when it was independent of the feeder system, free of stromal cells, and determined to maintain known patient tumor mutations. MGH119-R was derived in vitro from the treatment naive model, MGH119, through in vitro exposure to gefitinib, escalating from 10nM to a final concentration of 1μM.
2015-01-30 | E-GEOD-64322 | biostudies-arrayexpress
Project description:Tyrosine kinase inhibitors (TKIs) are effective treatments for non-small cell lung cancers (NSCLCs) with epidermal growth factor receptor (EGFR) mutations. However, they do not lead to cures, and, on average, relapse occurs typically occurs afterafter an average of one year of continuous treatment. In a subset of patients, aA fundamental histological transformation from NSCLC to small cell lung cancer (SCLC) is observed in a subset of the resistant cancers, but the molecular changes associated with this transformation remain unknown. Analysis of a cohort of tumor samples and cell lines derived from resistant EGFR mutant patients with SCLC transformation revealed that RB is lost in 100% of these SCLC transformed cases, but rarely in those that remain NSCLC. Global changes in gene expression, including increased neuroendocrine marker expression and absence of EGFR expression, are observed in resistant EGFR mutant cancers that transformed to SCLC. Consistent Further, with their similarities to classical SCLC at the genetic and gene expression levelincreased neuroendocrine marker and decreased EGFR expression as well as greater sensitivity to BCL2 family inhibition are observed in resistant SCLC transformed cancers compared to resistant NSCLCs. , cell lines derived from resistant EGFR mutant SCLC biopsies are substantially more sensitive to Bcl-2 family inhibition with ABT-263 compared to those derived from resistant EGFR mutant NSCLCs. Together, these findings suggest that despite developing initially as EGFR mutant adenocarcinomas, this subset of resistant cancers ultimately adopt many of the molecular and phenotypic characteristics of classical SCLC.
| EGAS00001001102 | EGA
Project description:EGFR tyrosine kinase inhibitors (EGFR-TKIs) induce a dramastic response in non-small cell lung cancer (NSCLC) patients with the EGFR mutation.However, acquired resistance to EGFR-TKIs in lung cancer cells
2017-11-11 | GSE106765 | GEO
Project description:Histologic transformation to small cell lung cancer (SCLC) is an increasingly common resistance mechanism to EGFR tyrosine kinase inhibitors in EGFR mutant lung adenocarcinoma (LUAD) that is underdiagnosed in clinical practice due to the requirement for tissue biopsy. Early and accurate detection of transformed (t)SCLC has important prognostic and therapeutic implications. To address this unmet need, we first comprehensively profiled the epigenomes of metastatic lung tumors finding widespread epigenomic reprogramming during histologic transformation from LUAD to SCLC. We then utilized a novel approach for epigenomic profiling of cell-free DNA, which discriminated patients with EGFR mutant tSCLC from patients with EGFR mutant LUAD with greater than 90% accuracy. This first demonstration of the ability to accurately, and non-invasively, detect small cell transformation in patients with EGFR mutant LUAD through epigenomic cfDNA profiling is a critical step towards a new paradigm of diagnostic and therapeutic precision for patients with advanced lung cancer.
2024-06-20 | GSE269746 | GEO
Project description:We established patient-derived cancer cell (PDC) cultures from metastatic non-small cell lung cancer, including two pairs of matched EGFR-mutant PDCs pre-treatment and after resistance to tyrosine-kinase inhibitors (TKIs), and then performed whole-exome and RNA sequencing to delineate their genomic architecture. For validation, we analyzed independent cohorts of primary NSCLC.
2019-12-31 | GSE135164 | GEO
Project description:Acquired drug resistance to tyrosine kinase inhibitor (TKI) targeted therapies remains a major clinical challenge. In EGFR mutant non-small cell lung cancer (NSCLC), therapeutic failure of EGFR TKIs can result from both genetic and epigenetic mechanisms of acquired drug resistance. Histologic and gene expression changes consistent with an epithelial-to-mesenchymal transition (EMT) have been associated with resistance to EGFR TKIs in both experimental models and in patients, and may coincide with genetic mechanisms of resistance such as the EGFRT790M gatekeeper mutation. While therapeutic approaches targeting EGFRT790M have been developed, a strategy for overcoming EMT-related resistance remains unclear. We performed whole-genome CRISPR screening on patient-derived, mesenchymal EGFRT790M-positive cell lines and identified FGFR1 as a critical gene promoting resistance to third generation EGFR TKIs. The FGFR1-3 inhibitor, BGJ398 (infigratinib), resensitized resistant mesenchymal-like cell lines to EGFR inhibition in a synergistic manner. Combining EGFR + FGFR inhibitors also inhibited the in vitro survival and expansion of EGFR mutant drug tolerant cells with mesenchymal-like features prior to the development of drug resistance, and delayed the development of in vivo resistance in EGFR mutant NSCLC xenograft tumors. These results suggest that dual EGFR + FGFR blockade may be a promising clinical strategy for preventing and overcoming EMT-associated acquired drug resistance in EGFR mutant NSCLC.
2019-04-30 | GSE114647 | GEO
Project description:Although tyrosine kinase inhibitors (TKIs) targeting Epidermal Growth Factor Receptor (EGFR) activating mutations have significantly improved outcomes in EGFR-mutant non-small cell lung cancer, resistance inevitably develops. Despite the heterogeneity of resistance mechanisms, many induce activation of MAPK signaling in the presence of EGFR-TKIs. ARAF gene amplification is identified as one such mechanism that activates MAPK signaling by directly interacting with RAS, yet its clinicopathologic characteristics remain poorly understood. We characterized five cases with ARAF amplification resistant to first- or second-generation EGFR-TKIs and screened an additional 48 re-biopsied specimens following resistance to Osimertinib. Among Osimertinib-resistant tumors, we identified four cases with ARAF amplification. Overall, these nine ARAF-amplified resistant tumors retained their original founder EGFR mutation and lacked secondary alterations. Furthermore, we identified two cases showing histologic transformation from lung adenocarcinoma to small cell lung cancer (SCLC). SCLC can be classified into four subtypes defined by transcriptional signatures driven by specific transcription factors. To estimate the subtypes of these resistant tumors, RNA sequencing analysis was performed in paired samples before and after treatment with EGFR-TKIs.
2024-10-30 | GSE274293 | GEO