Targeting the NRG1/HER3 pathway in tumor cells and cancer-associated fibroblasts with an anti-neuregulin 1 antibody inhibits tumor growth in pre-clinical models of pancreatic cancer

Ogier, Charline; Colombo, Pierre‐Emmanuel; Bousquet, Corinne; Canterel-Thouennon, Lucile; Sicard, Pierre; Garambois, Véronique; Thomas, Gaëlle; Gaborit, Nadège; Jarlier, Marta; Pirot, Nelly; Pugnière, Martine; Vie, Nadia; Gongora, Céline; Martineau, Pierre; Robert, Bruno; Pèlegrin, André; Chardès, Thierry; Larbouret, Christel

doi:10.1016/j.canlet.2018.06.023

Cited by 40 publications

(24 citation statements)

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“…They play pivotal roles in tumor progression in various types of tumor, such as lung cancer, 5 breast cancer, 6 pancreatic cancer. 7 CAFs are involved in many physiological processes such as epithelial-mesenchymal transition (EMT), chemoresistance, matrix remodeling, metastasis and immunosuppression by secreting cytokines and growth factors and creating an optimal microenvironment for tumor cells. 8,9 Although people have made great achievement on understanding the mechanisms of chemotherapy on tumor cells, the mechanisms underlying the effect of chemotherapy on TME remains unelucidated.…”

Section: Introductionmentioning

confidence: 99%

<p>The Metastasis Potential Promoting Capacity of Cancer-Associated Fibroblasts Was Attenuated by Cisplatin via Modulating KRT8</p>

Song¹,

Guo²,

Wang³

et al. 2020

OTT

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Background: Cancer-associated fibroblasts (CAFs) are an essential component of tumor microenvironment. They are attracting increasing attentions due to their crucial role in tumor growth, drug-resistance and metastasis. Cisplatin is a first-line chemotherapy drug applying in various types of cancer. There are intensive studies on cisplatin's effect on tumor cells, however, its effect on CAFs remains poorly understood. In the present study, we investigated the effect of cisplatin on CAFs. Methods: Cell migration was detected by wound healing assay. Cell invasion was performed by the transwell assay. mRNA expression was detected by quantitative PCR, and protein expression was detected by Western blotting. Tumor growth was measured using BALB/c nude mice tumor models. Results: Cisplatin attenuated the promoting capacity of CAFs on lung cancer cell migration and invasion, via suppressing CAFs' effect on metastasis-related genes including Twist1, vascular endothelial growth factor receptor (VEGFR), MMP2, and AKT signaling pathway. Keratin 8 (KRT8) was identified as a target of cisplatin. KRT8 upregulation in CAFs is responsible for the inhibitory effect of cisplatin on lung cancer cells metastasis potential through AKT pathway suppression. The stimulation of AKT by AKT activator SC79 reversed KRT8's effect on cell migration. Importantly, in vivo study also showed that CAFs enhanced tumor growth significantly, and cisplatin effectively abrogated the promoting effect of CAFs on tumor growth. Conclusion: Our results revealed a novel mechanism that cisplatin attenuated the metastasis promoting effect of CAFs via KRT8/AKT signaling pathway. This finding highlights KRT8 in CAFs as a potential therapeutic candidate for metastasis treatment.

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Section: Introductionmentioning

confidence: 99%

<p>The Metastasis Potential Promoting Capacity of Cancer-Associated Fibroblasts Was Attenuated by Cisplatin via Modulating KRT8</p>

Song¹,

Guo²,

Wang³

et al. 2020

OTT

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“…Despite the fact that the prognosis of HER2 overexpressing metastatic breast cancer has been significantly improved with Trastuzumab therapy, more efficient therapies are necessary for relapsing or resistant cases. Heregulin rescues the cancer cells from the inhibitory effects of HER2 kinase antagonists through HER3 activation 33 . Moreover, the HER3 mediates resistance to the inhibitory effect of HER2, EGFR, and PI3K kinase inhibitors via HER3 up-regulation and activation 34 .…”

Section: Discussionmentioning

confidence: 99%

A novel anti-HER2 antibody GB235 reverses Trastuzumab resistance in HER2-expressing tumor cells in vitro and in vivo

Shu

Yan

Xu³

et al. 2020

Sci Rep

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HER2 overexpression is frequently associated with tumor metastasis and poor prognosis of breast cancer. More evidence indicates that HER3 is involved in HER2-resistant therapies. Combination treatments with two or more different monoclonal antibodies are a promising strategy to overcome resistance to HER2 therapies. We presented a novel fully human HER2-targeted monoclonal antibody, GB235, screened from a phage-display library against the HER2 antigen. GB235 in combination with Trastuzumab overcomes resistance in HER2-positive tumors and results in more sustained inhibition of tumor growth over time. The competition binding assay showed that the epitopes of GB235 do not overlap with those of Pertuzumab and Trastuzumab on HER2. Further HER2 mutagenesis results revealed that the binding epitopes of GB235 were located in the domain III of HER2. The mechanism of action of GB235 in blocking HER2-driven tumors is different from the mechanisms of Trastuzumab or Pertuzumab. GB235 does not affect the heterodimerization of HER2 and HER3, whereas the GB235 combined treatment with Trastuzumab significantly inhibited heregulin-induced HER3 phosphorylation and downstream signaling. Moreover, GB235 in combination with Trastuzumab reversed the resistance to heregulin-induced proliferation in HER2-overexpressing cancer cell lines. GB235 combined with Trastuzumab treatment in xenograft models resulted in improved antitumor activity. Complete tumor suppression was observed in the HER2-positive NCI-N87 xenograft model treated with the combination treatment with GB235 and Trastuzumab. In a Trastuzumab-resistant patient-derived tumor xenograft model GA0060, GB235 plus Trastuzumab reversed the resistance to Trastuzumab monotherapy. Because GB235 showed a different working mechanism with Pertuzumab and Trastuzumab, these agents can be considered complementary therapy against HER2 overexpression tumors.www.nature.com/scientificreports www.nature.com/scientificreports/ to HER2 ECD proteins of three different species. GB235 specifically bound to human and rat HER2 ECD, but did not cross-react with the mouse HER2 ECD in the ELISA (Fig. 6C). Moreover, it was observed that 362D, 374Q, 395D, 456 H are phylogenetically conserved in human and rat HER2 ECD d III , but not in mouse HER2 ECD d III . The residues are conserved in the human and rat HER2 but not in the mouse HER2, thus explaining the lack of cross-reaction with mouse HER2. The binding of the full-length human HER2 ECD d I-IV to GB235 was abolished in site-directed mutants of human HER2 (D362N, Q374H and H456N) (Fig. 6D). The residues 362D, 374Q and 456 H in the human HER2 ECD d III were found to be critical for the binding of GB235.

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“…It inhibits migration and growth of pancreatic cancer cells that are co-cultured with CAFs both in experimental models of pancreatic cancer. Studies shows that 7E3 could be a promising antibody mediated approach to targeting the relationship between pancreatic cancer and CAFs [99]. Src kinase expression from fibroblasts supports invasion and metastases of pancreatic cancer.…”

Section: Modulation Of Cafs To Treat Pancreatic Cancermentioning

confidence: 99%

Pancreatic Cancer Associated Fibroblasts (CAF): Under-Explored Target for Pancreatic Cancer Treatment

Norton

Foster

Chinta

et al. 2020

Cancers

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Pancreatic cancer is the 4th leading cause of cancer deaths in the United States. The pancreatic cancer phenotype is primarily a consequence of oncogenes disturbing the resident pancreas parenchymal cell repair program. Many solid tumor types including pancreatic cancer have severe tumor fibrosis called desmoplasia. Desmoplastic stroma is coopted by the tumor as a support structure and CAFs aid in tumor growth, invasion, and metastases. This stroma is caused by cancer associated fibroblasts (CAFs), which lay down extensive connective tissue in and around the tumor cells. CAFs represent a heterogeneous population of cells that produce various paracrine molecules such as transforming growth factor-beta (TGF-beta) and platelet derived growth factors (PDGFs) that aid tumor growth, local invasion, and development of metastases. The hard, fibrotic shell of desmoplasia serves as a barrier to the infiltration of both chemo- and immunotherapy drugs and host immune cells to the tumor. Although there have been recent improvements in chemotherapy and surgical techniques for management of pancreatic cancer, the majority of patients will die from this disease. Therefore, new treatment strategies are clearly needed. CAFs represent an under-explored potential therapeutic target. This paper discusses what we know about the role of CAFs in pancreatic cancer cell growth, invasion, and metastases. Additionally, we present different strategies that are being and could be explored as anti-CAF treatments for pancreatic cancer.

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Targeting the NRG1/HER3 pathway in tumor cells and cancer-associated fibroblasts with an anti-neuregulin 1 antibody inhibits tumor growth in pre-clinical models of pancreatic cancer

Cited by 40 publications

References 40 publications

<p>The Metastasis Potential Promoting Capacity of Cancer-Associated Fibroblasts Was Attenuated by Cisplatin via Modulating KRT8</p>

<p>The Metastasis Potential Promoting Capacity of Cancer-Associated Fibroblasts Was Attenuated by Cisplatin via Modulating KRT8</p>

A novel anti-HER2 antibody GB235 reverses Trastuzumab resistance in HER2-expressing tumor cells in vitro and in vivo

Pancreatic Cancer Associated Fibroblasts (CAF): Under-Explored Target for Pancreatic Cancer Treatment

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