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CRISPR library knockout screening identified candidate genes whose loss of function confers lapatinib resistance in HER2-amplified GC cells.

ABSTRACT: CRISPR library knockout screening identified candidate genes whose loss of function confers lapatinib resistance in HER2-amplified GC cells.

PROVIDER: PRJNA625316 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR11545713.fastq.gz	Fastqsanger.gz
	SRR11545714.fastq.gz	Fastqsanger.gz
	SRR11545715.fastq.gz	Fastqsanger.gz
	SRR11545716.fastq.gz	Fastqsanger.gz
	SRR11545717.fastq.gz	Fastqsanger.gz

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CRISPR library knockout screening identified candidate genes whose loss of function confers lapatinib resistance in HER2-amplified GC cells.

Project description:To identify genes, whose loss of function confers drug resistance to lapatinib, we performed a genome-wide CRISPR/Cas9 gene knockout screening in two human gastric cancer cell lines harboring HER2 amplification, N87 and OE19, respectively. By performing this study, we identiied a goup of genes associated with lapatinib resistance in HER2-amplified gastric cancer.

2021-08-24 | GSE148668 | GEO

Ontogeny and Vulnerability of Lapatinib Drug-Tolerant Persisters in HER2-positive Breast Cancer

Project description:Despite advances in HER2-targeted therapeutics, resistance remains a significant clinical problem in HER2-positive (HER2+) breast cancer, especially in the metastatic setting. Drug-tolerant persisters (DTPs), a sub-population of cancer cells that survive via reversible, non-genetic mechanisms, are implicated in resistance to tyrosine kinase inhibitors (TKIs) in several cancer models, but DTPs for HER2-targeted TKIs have not been characterized extensively. We found that upon treatment with the TKI lapatinib, HER2+ breast cancer lines yielded DTPs with luminal-like or mesenchymal-like transcriptional programs and differential sensitivity to lapatinib/anti-estradiol combinations. Lentiviral barcoding and single cell RNA-sequencing indicate that HER2+/ER+ cells cycle stochastically through a pre-DTP state, characterized by a G0-like signature, which uniquely gives rise to DTPs upon lapatinib exposure.

2021-12-13 | GSE156246 | GEO

Adaptive responses of the HER2+ SKBR-3 and BT474m1 cell lines to lapatinib and JQ1

Project description:SKBR-3 or BT474m1 HER2+ breast cancer cells were treated with either DMSO, 300nM lapatinib, 300nM JQ1, or lapatinib and JQ1 in combination for 48h.

2020-10-26 | GSE160018 | GEO

SKBR3/HER2+ Breast Cancer Cellular Response to Lapatinib and Ipatasertib Kinase Inhibitors

Project description:To explore the broader impact of kinase inhibitors on breast cancer cells, SKBR3/HER2+ cells were treated with two small molecule drugs, i.e., Lapatinib (10 uM) - a Tyr kinase inhibitor, and Ipatasertib (1 uM) - a Ser/Thr kinase inhibitor. Serum-starved cells (24 h) were exposed for 36 h to Lapatinib/EGF or a combination of Lapatinib/Ipatasertib/EGF. EGF - only stimulated cells were used as control. The EGF concentration was 10 nM throughout all experiments. Proteomic profiles of nuclear and cytoplasmic cell fractions of treated vs non-treated cells were generated by nano-LC-MS/MS using an Orbitrap QE instrument.

2024-08-23 | PXD051094 | Pride

Integrative proteo-genomic profiling uncovers key biomarkers of lapatinib resistance in HER2-positive breast cancer

Project description:To understand the transcriptomic, genomic and proteomics changes between HER2 overexpressingcells and those that have become resistant to lapatinib

2025-11-17 | PXD056848 | Pride

A Phase II Randomized Trial of Neoadjuvant Trastuzumab or Lapatinib or the Combination of Trastuzumab and Lapatinib, Followed by Docetaxel and Carboplatin with Trastuzumab and/or Lapatinib in Patients with HER2+ Breast Cancer [treatments]

Project description:Adjuvant docetaxel, carboplatin, and trastuzumab (TCH) is a standard regimen for HER2+ breast cancer. Dual HER2-blockade with lapatinib (L) and trastuzumab demonstrated significant activity in the metastatic and neoadjuvant settings. This study evaluates neoadjuvant TC plus trastuzumab (H) and/or lapatinib (L). This study demonstrated a similar pCR rate with TCH and TCHL and a lower rate of pCR with TCL. Treatment-related toxicity limited the ability for participants to receive protocol-specified chemotherapy and HER2-targeted therapy in the TCHL Arm.

2019-05-08 | GSE130787 | GEO

2019-05-08 | GSE130786 | GEO

Lapatinib-Induced Enhancement Of Mitochondrial Respiration In HER2-Positive SK-BR-3 Cells: Mechanism Revealed By Analysis Of Proteomic But Not Transcriptomic Data

Project description:Dual inhibitors of HER2 and EGFR, such as lapatinib, have shown significant efficacy for the therapy of HER2-positive breast cancer. Previous experiments showed that in cell cultures, the efficacy of lapatinib was significantly reduced by exposure to human serum and human epidermal growth factor (EGF). At the proteomic and transcriptomic levels, we examined the changes in the HER2-positive breast cancer cell line SK-BR-3 profiles upon treatment with lapatinib, either alone or in combination with human serum or EGF. Proteomic profiling revealed 350 differentially expressed proteins (DEPs) in response to lapatinib treatment at concentrations that induced cell growth arrest. Addition of human serum or EGF in combination with lapatinib prevented cell growth inhibition, and this combination treatment returned the expression of ~93% of DEPs to drug-free levels for both human serum and EGF. Gene ontology enrichment and OncoboxPD pathway activation level analysis showed that lapatinib addition influenced mostly common functional processes revealed in RNA- and protein-based assays. However, a specific feature was observed at the proteome level: addition of lapatinib increased the expression of proteins associated with mitochondrial function and cellular respiration. This feature was not observed when using RNA sequencing data for the same experiments. However, it is consistent with the results of the resazurin test, which showed a 1.8-fold increase in SK-BR-3 cellular respiration upon exposure to lapatinib. Thus, we conclude that enhanced cellular respiration is a novel additional mechanism of action of lapatinib on HER2-positive cancer cells.

2024-09-26 | PXD054180 | Pride

FOXA1-dependent responses of the HER2+ SKBR-3 cell line to lapatinib

Project description:SKBR-3 HER2+ breast cancer cells were treated with 25 nM Dharmacon siGENOME non-targeting (NT) siRNA control pool or siRNA pool targeting FOXA1 for 48h, then treated with either DMSO or 300nM lapatinib for 24h.

2020-10-26 | GSE160001 | GEO

HER2-positive breast cancer cells resistant to trastuzumab and lapatinib lose reliance upon HER2 and are sensitive to the multitargeted kinase inhibitor sorafenib

Project description:HER2 targeting with trastuzumab has changed the prognosis of breast cancer patients carrying amplification and/or overexpression of this oncogene. Despite this progress, however, resistance to trastuzumab occurs in the vast majority of patients. Newer anti-HER2 therapies, like the dual tyrosine-kinase inhibitor (TKI) lapatinib, show antitumor activity in a limited proportion of patients, indicating that HER2 can be still exploited as a target after trastuzumab failure. However, due to the high proportion of patients that fail to respond to these alternative strategies, it is reasonable to assume that cells escaping HER2 targeting may rely on alternative pathways not involving HER2 to sustain their growth. Their knowledge is relevant for exploiting new therapies. To investigate this hypothesis we generated a human HER2 overexpressing breast cancer cell line resistant to trastuzumab and lapatinib (T100) and we have characterized it genetically and molecularly. In T100 cells, the previously proposed mechanisms of resistance to HER2 inhibitors did not explain cell escape. Notably, silencing HER2 by shRNA did not affect the growth of T100 cells, suggesting loss of reliance upon HER2. Among the alternative pathways that we explored, altered levels of the antiapoptoptic proteins Mcl-1 and Survivin were observed. This suggested the possibility of targeting resistant cells with the multitarget inhibitor sorafenib. Moreover, sorafenib, nearly inactive in parental cells, strongly inhibited the in vitro growth of T100 cells. In conclusion, we provide a new model where the activation of HER2 independent mechanisms sustains the growth of tumor cells, significantly increasing the sensitivity to sorafenib. Keywords: HER2, breast cancer, resistance, trastuzumab, lapatinib, sorafenib

2010-12-15 | GSE17630 | GEO

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