Neoadjuvant sintilimab plus chemotherapy in early-stage EGFR-mutant NSCLC: phase 2 trial interim results (NEOTIDE/CTONG2104)
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ABSTRACT:
PROVIDER: PRJNA1010782 | ENA |
REPOSITORIES: ENA
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Project description:We launched an investigator-initiated, Simon’s two-stage design trial of neoadjuvant sintilimab combined with carboplatin and nab-paclitaxel (nab-PC) in early-stage EGFR-mutant NSCLC (Clinicaltrial.gov number NCT05244213). Here we report the first interim results of stage 1 cohort which met the overall primary endpoint in advance, and multi-omics profiling of neoadjuvant immunotherapy combination in early-stage EGFR-mutant patients. We performed in-depth single-cell RNA/TCR sequencing (scRNA/TCR-seq) of cells derived from 11 resected tumors as well as 34 tumors from real-world cohort which were all confirmed wild-type lung adenocarcinoma (LUAD) or adeno-squamous carcinoma (ASC) and received neoadjuvant immunochemotherapy as control. By associating the tumor microenvironment (TME) and with responses, we uncovered heterogeneous mechanisms of primary resistance, providing insights into further strategic developments of combination regimens to improve the clinical outcome of EGFR-mutant NSCLC patients.
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Project description:Non-small cell lung cancers (NSCLCs) harboring activating EGFR mutants show dramatic responses to EGFR TKIs, such as erlotinib and geffitinib. However, nearly all patients show relapse within 1 year after initial treatment. We used microarrays to detail global gene expression changes in EGFR mutant cells vs. WT cells responding to erlotinib. 4 EGFR mutant and 4 WT NSCLC cells were treated with or without erlotinib for 24 hr, followed by RNA extraction and hybridization on Affymetrix microarrays.
2014-05-16 | E-GEOD-57156 | biostudies-arrayexpress
Project description:Non-small cell lung cancer (NSCLC) lung adenocarcinoma (LUAD) is a leading cause of death worldwide. Activating mutations in the tyrosine kinase domain of the oncogene epidermal growth factor receptor (EGFR) are responsible for ~10-50% of all LUAD cases. Although EGFR tyrosine kinase inhibitors (TKIs) have been effective in prolonging NSCLC patient survival and quality of life, acquired resistance mechanisms and disease progression are inevitable. Contemporary second- and third-line treatments, such as immunotherapy, remain ineffective for these patients, presenting a clear and unmet need for alternative or adjuvant therapeutics for the treatment of mutant EGFR positive NSCLC. Here we show that an anti-EGFR aptamer (EGFRapt) decreases viability of NSCLC cell lines harboring the L858R ± T790M mutation in EGFR but not cell lines harboring wild-type or exon 19 deletions. In a humanized xenograft mouse model, EGFRapt decreased tumor burden compared to controls when delivered intratumorally over multiple doses. To elucidate the mechanism by which EGFRapt exerts these effects, we examined kinase-dependent and kinase-independent mechanisms and found that it is cell line dependent, either inhibiting cellular proliferation or inducing cell death. Post hoc transcriptomics analysis comparing EGFRapt to control aptamer or vehicle validated these findings and provided additional mechanistic insights. Overall, these data establish that EGFRapt has direct anti-cancer activity in mutant EGFR positive NSCLC via targetable mechanisms that are independent of existing approaches and provide a foundation for further development of nucleic acid-based therapies that target EGFR.
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Project description:Bidkhori2012 - EGFR signalling in NSCLC
The paper describes and compares two models on EGFR signalling between normal and NSCLC cells. Moreover, it is shown that ERK (MAPK), STAT and Akt factor's activation pattern are different between normal and NSCLA models. This model corresponds to EGFR signalling in NSCLA cells.
Created by The MathWorks, Inc. SimBiology tool, Version 3.3
This model is described in the article:
Modeling of tumor progression in NSCLC and intrinsic resistance to TKI in loss of PTEN expression.
Bidkhori G, Moeini A, Masoudi-Nejad A
PloS one [2012, 7(10):e48004]
Abstract:
EGFR signaling plays a very important role in NSCLC. It activates Ras/ERK, PI3K/Akt and STAT activation pathways. These are the main pathways for cell proliferation and survival. We have developed two mathematical models to relate to the different EGFR signaling in NSCLC and normal cells in the presence or absence of EGFR and PTEN mutations. The dynamics of downstream signaling pathways vary in the disease state and activation of some factors can be indicative of drug resistance. Our simulation denotes the effect of EGFR mutations and increased expression of certain factors in NSCLC EGFR signaling on each of the three pathways where levels of pERK, pSTAT and pAkt are increased. Over activation of ERK, Akt and STAT3 which are the main cell proliferation and survival factors act as promoting factors for tumor progression in NSCLC. In case of loss of PTEN, Akt activity level is considerably increased. Our simulation results show that in the presence of erlotinib, downstream factors i.e. pAkt, pSTAT3 and pERK are inhibited. However, in case of loss of PTEN expression in the presence of erlotinib, pAkt level would not decrease which demonstrates that these cells are resistant to erlotinib.
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2024-09-02 | BIOMD0000000453 | BioModels
Project description:The clinical efficacy of neoadjuvant immunotherapy plus chemotherapy remains elusive in localized epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC). Here, we report interim results of a Simon's two-stage design, phase 2 trial using neoadjuvant sintilimab with carboplatin and nab-paclitaxel in resectable EGFR-mutant NSCLC. All 18 patients undergo radical surgery, with one patient experiencing surgery delay. Fourteen patients exhibit confirmed radiological response, with 44% achieving major pathological response (MPR) and no pathological complete response (pCR). Similar genomic alterations are observed before and after treatment without influencing the efficacy of subsequent EGFR-tyrosine kinase inhibitors (TKIs) in vitro. Infiltration and T cell receptor (TCR) clonal expansion of CCR8+ regulatory T (Treg)hi/CXCL13+ exhausted T (Tex)lo cells define a subtype of EGFR-mutant NSCLC highly resistant to immunotherapy, with the phenotype potentially serving as a promising signature to predict immunotherapy efficacy. Informed circulating tumor DNA (ctDNA) detection in EGFR-mutant NSCLC could help identify patients nonresponsive to neoadjuvant immunochemotherapy. These findings provide supportive data for the utilization of neoadjuvant immunochemotherapy and insight into immune resistance in EGFR-mutant NSCLC.
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Project description:We have employed a transcriptomic approach to find a molecular target that could compensate for the loss of EGFR signaling in NSCLC cell lines with acquired resistance to gefitinib with an EMT phenotype.
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Project description:In this study, to investigate the underlying molecular mechanisms of how EGFR-TKIs resistance occurs in NSCLC, we examined gene expression using microarray technology on gefitinib-resistant NSCLC cells to obtain differentially expressed (DE) lncRNAs and mRNAs. Then we carried out KEGG enrichment analysis for DE-mRNAs and constructed the ceRNA regulatory network of DE-lncRNAs and DE-mRNAs. Our results revealed the downregulated lncRNA LINC01128 acted as ceRNA to decrease PTEN via sponging miR-25-3p, and then the signal reactions caused by the reduction of PTEN would activate PI3K/Akt signaling pathway, which may lead to the development of drug resistance to EGFR-TKIs in NSCLC. Our findings will provide a novel perspective for the underlying molecular mechanisms of EGFR-TKIs resistance in NSCLC. Besides, this research will help to develop new therapeutic targets for EGFR-TKIs resistance in NSCLC.
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