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RC48 Plus Tislelizumab, Low-dose Capecitabine and Celecoxib for HER2-positive Metastatic Colorectal Cancer

ABSTRACT: As an established therapeutic target, HER2 is widely used in a variety of tumors, including breast cancer and gastric cancer, among which a variety of drugs, including trastuzumab, lapatinib and T-DM1, have been approved for the treatment of breast cancer and gastric cancer with HER2 amplification or overexpression. In colorectal cancer, HER2 as a target has also been focused in recent years.

DISEASE(S): Colorectal Cancer,Colorectal Neoplasms

PROVIDER: 2751274 | ecrin-mdr-crc |

REPOSITORIES: ECRIN MDR

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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

Analysis of HER2 genomic binding in breast cancer cells identifies a global role in direct gene regulation

Project description:HER2 is a transmembrane receptor tyrosine kinase, which plays a key role in breast cancer due to a common genomic amplification. It is used as a marker to stratify patients in the clinic and is targeted by a number of drugs including Trastuzumab and Lapatinib. HER2 has previously been shown to translocate to the nucleus. In this study, we have explored the properties of nuclear HER2 by analysing the binding of this protein to the chromatin in three breast cancer cell lines. We find genome-wide re-programming of HER2 binding after treatment with the growth factor EGF. Over 4,000 HER2 binding sites are found in all three breast cancer cell lines, and these occur near genes involved in protein kinase activity and signal transduction. HER2 was shown to co-localise at a subset of regions demarcated by H3K4me1, a hallmark of functional enhancer elements and HER2/H3K4me1 co-bound regions were enriched near EGF regulated genes providing evidence for their functional role as regulatory elements. A chromatin bound role for HER2 was verified by independent methods, including Proximity Ligation Assay (PLA), which confirmed a close association between HER2 and H3K4me1. Interestingly, HER2 bound to the ErbB2 gene itself indicating a potential self-regulatory mechanism for HER2. Mass spectrometry analysis of the chromatin bound HER2 complex identified EGFR and STAT3 as interacting partners. These findings reveal a global role for HER2 as a chromatin-associated factor that binds to enhancer elements to elicit direct gene expression events in breast cancer cells.

2020-05-26 | PXD003915 | Pride

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

DUSP6 inhibition overcomes Neuregulin/HER3-driven therapy resistance in HER2+ breast cancer [BT474]

Project description:To investigate transcriptomic changes during development of resistance to lapatinib in a HER2+ breast cancer cell line We performed gene expression profiling analysis using data obtained from RNA-seq of 4 different stage of development of lapatinib resistance in a HER2+ breast cancer cell line

2024-04-13 | GSE231525 | GEO

Human breast cancer cells: parental v.s lapatinib-resistant clone

Project description:Transcriptional profiling of human HER2-positive BT474 breast cancer cells comparing control untreated cancer cells with lapatinib-resistant clone established by chronic treatment with lapatinib

2013-10-31 | GSE51889 | GEO

The Ontogeny and Vulnerabilities of Lapatinib Drug Tolerant Persisters [Parental (P) vs. Drug-Tolerant Persister (DTP)]

Project description:Despite significant advances in HER2-targeted therapies, therapeutic resistance in HER2-positive (HER2+) breast cancer remains a significant clinical problem, 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 (e.g., lapatinib, neratinib, tucatinib) have not been characterized extensively. Here, we report that HER2+ER+ and HER2+ER- breast cancer lines give rise to distinct types of “lapatinib-DTPs,” characterized by different transcriptional programs and sensitivity to lapatinib/anti-estradiol combination. Lapatinib-DTPs from HER2+/ER+ cells rewire the PI3K/AKT/mTORC1 pathway via transcriptional induction of SGK3 to enable AKT-independent mTORC1 activation and survival. Lentiviral barcoding experiments, combined with single cell RNA-sequencing, suggest that HER2+ cells stochastically cycle through a cell state (“pre-DTP”) capable of transition to DTPs. Collectively, our results provide insight into DTP ontogeny and therapeutic vulnerabilities.

2021-12-31 | GSE155341 | GEO

The Ontogeny and Vulnerabilities of Lapatinib Drug Tolerant Persisters [NPY1R]

2021-12-31 | GSE155227 | GEO

Human breast cancer cells: parental v.s lapatinib-resistant clone

2013-10-31 | E-GEOD-51889 | biostudies-arrayexpress

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

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

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