scholarly journals Genomic and transcriptomic determinants of therapy resistance and immune landscape evolution during anti-EGFR treatment in colorectal cancer

2018 ◽  
Author(s):  
Andrew Woolston ◽  
Khurum Khan ◽  
Georgia Spain ◽  
Louise J Barber ◽  
Beatrice Griffiths ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Growth Factor ◽  
Prospective Trial ◽  
Genetic Resistance ◽  
Growth Factor Receptor ◽  
Therapy Resistance ◽  
Wild Type ◽  
Epidermal Growth ◽  
Novel Associations

AbstractAnti-epidermal growth factor receptor (EGFR) antibodies (anti-EGFR-Ab) are effective in a subgroup of patients with metastatic colorectal cancer (CRC). We applied genomic and transcriptomic analyses to biopsies from 35 RAS wild-type CRCs treated with the anti-EGFR-Ab cetuximab in a prospective trial to interrogate the molecular resistance landscape. This validated transcriptomic CRC-subtypes as predictors of cetuximab benefit; identified novel associations of NF1-inactivation and non-canonical RAS/RAF-aberrations with primary progression; and of FGF10- and non-canonical BRAF-aberrations with AR. No genetic resistance drivers were detected in 64% of AR biopsies. The majority of these had switched from the cetuximab-sensitive CMS2-subtype pretreatment to the fibroblast- and growth factor-rich CMS4-subtype at progression. Fibroblast supernatant conferred cetuximab resistance in vitro, together supporting subtype-switching as a novel mechanism of AR. Cytotoxic immune infiltrates and immune-checkpoint expression increased following cetuximab responses, potentially providing opportunities to treat CRCs with molecularly heterogeneous AR with immunotherapy.

scholarly journals HER2 Expression Is Predictive of Survival in Cetuximab Treated Patients with RAS Wild Type Metastatic Colorectal Cancer

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 638
Author(s):  
Said A. Khelwatty ◽  
Soozana Puvanenthiran ◽  
Sharadah Essapen ◽  
Izhar Bagwan ◽  
Alan M. Seddon ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Family Members ◽  
Growth Factor Receptor ◽  
Wild Type ◽  
Her Family ◽  
Epidermal Growth ◽  
Metastatic Sites

The overexpressed HER2 is an important target for treatment with monoclonal antibody (mAb) trastuzumab, only in patients with breast and gastric cancers, and is an emerging therapeutic biomarker in metastatic colorectal cancer (mCRC) treated with anti-epidermal growth factor receptor (EGFR) mAbs cetuximab and panitumumab. In this study, we investigated the relative expression and predictive value of all human epidermal growth factor receptor (HER) family members in 144 cetuximab-treated patients with wild type RAS mCRC. The relative expression of EGFR and HER2 have also been examined in 21-paired primary tumours and their metastatic sites by immunohistochemistry. Of the 144 cases examined, 25%, 97%, 79%, 48%, and 10% were positive for EGFR, HER2, HER3, and HER4 and all four HER family members, respectively. The expression of EGFR was an indicator of poorer overall survival and the membranous expression of HER2 and HER3 3+ intensity was associated with a shorter progression free survival (PFS). In contrast, the cytoplasmic expression of HER2 was associated with better PFS. In 48% and 71% of the cases, there were discordance in the expression of EGFR or one or more HER family members in paired primary and related metastatic tumours, respectively. Our results implicate the importance of a large prospective investigation of the expression level and predictive value of not only the therapeutic target (i.e., EGFR protein) but also HER2 and other HER family members as therapeutic targets, or for response to therapy with anti-EGFR mAbs and other forms of HER inhibitors, in both the primary tumours and metastatic sites in mCRC.

Liver endothelium promotes HER3-mediated cell survival in KRAS wild-type and mutant colorectal cancer cells

2021 ◽  
Author(s):  
Moeez Rathore ◽  
Michel'le Wright ◽  
Rajat Bhattacharya ◽  
Fan Fan ◽  
Ali Vaziri-Gohar ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Cell Survival ◽  
Growth Factor Receptor ◽  
Wild Type ◽  
Mutation Status ◽  
Her Family ◽  
Epidermal Growth

Abstract We previously showed that human epidermal growth factor receptor 3 (HER3, also known as ERBB3) is a key mediator in liver endothelial cell (EC) promoting colorectal cancer (CRC) growth and chemoresistance, and suggested HER3-targeted therapy as a strategy for treating patients with metastatic CRC (mCRC) in the liver. Meanwhile, KRAS mutations occur in 40–50% of mCRC and render CRC resistant to therapies targeting the other HER family protein epidermal growth factor receptor (EGFR). It is necessary to elucidate the roles of KRAS mutation status in HER3-mediated cell survival and CRC response to HER3 inhibition. In the present study, we demonstrated that liver EC-secreted factors activated HER3 and promoted cell survival in KRAS wild-type and mutant CRC cells and tumors, and that blocking HER3 with an antibody, seribantumab, blocked EC-induced CRC survival. Our findings highlight a potential of utilizing HER3-targeted therapies for treating patients with mCRC regardless of KRAS mutation status.

scholarly journals Epidermal Growth Factor Receptor as Target for Perioperative Elimination of Circulating Colorectal Cancer Cells

2022 ◽  
Vol 2022 ◽  
pp. 1-13
Author(s):  
Mandy Gruijs ◽  
Rens Braster ◽  
Marije B. Overdijk ◽  
Tessa Hellingman ◽  
Sandra Verploegen ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Liver Metastasis ◽  
Tumor Cells ◽  
Growth Factor Receptor ◽  
Metastasis Development ◽  
Epidermal Growth ◽  
Colorectal Cancer Patients

Surgical resection of the tumor is the primary treatment of colorectal cancer patients. However, we previously demonstrated that abdominal surgery promotes the adherence of circulating tumor cells (CTC) in the liver and subsequent liver metastasis development. Importantly, preoperative treatment with specific tumor-targeting monoclonal antibodies (mAb) prevented surgery-induced liver metastasis development in rats. This study investigated whether the epidermal growth factor receptor (EGFR) represents a suitable target for preoperative antibody treatment of colorectal cancer patients undergoing surgery. The majority of patients with resectable colorectal liver metastases were shown to have EGFR + CTCs. Three different anti-EGFR mAbs (cetuximab, zalutumumab, and panitumumab) were equally efficient in the opsonization of tumor cell lines. Additionally, all three mAbs induced antibody-dependent cellular phagocytosis (ADCP) of tumor cells by macrophages at low antibody concentrations in vitro, independent of mutations in EGFR signaling pathways. The plasma of cetuximab-treated patients efficiently opsonized tumor cells ex vivo and induced phagocytosis. Furthermore, neither proliferation nor migration of epithelial cells was affected in vitro, supporting that wound healing will not be hampered by treatment with low anti-EGFR mAb concentrations. These data support the use of a low dose of anti-EGFR mAbs prior to resection of the tumor to eliminate CTCs without interfering with the healing of the anastomosis. Ultimately, this may reduce the risk of metastasis development, consequently improving long-term patient outcome significantly.

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