Oncogenic ERBB2 aberrations and KRAS mutations cooperate to promote pancreatic ductal adenocarcinoma progression

Li, Zhang; Shao, Chenghao; Liu, Huan; Lu, Xiao-Jing; Xing, Jia; Zheng, Xufen; Wang, Simin; Zhu, Li; Li, Ke; Pang, Yu; Xie, Feifei; Lu, Yuan; Wang, Yuexiang

doi:10.1093/carcin/bgz086

Cited by 15 publications

(20 citation statements)

References 49 publications

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“…Recently, ERBB2 amplification and gain-of-function mutations have been identified in human PDAC patients, and mutations of ERBB2 and KRAS co-occur. Cell culture studies revealed that inhibition of ERBB2 in PDAC cell lines overexpressing ERBB2 represses proliferation and invasion 34 . Finally, heterogeneous expression of EGFR was detected in a mouse model of PDAC with Kras G12D and Tp53 R172H mutations, whereas ERBB2 expression and ERK activation were elevated and homogeneous in PanIN, PDAC and metastases 6 .…”

Section: Discussionmentioning

confidence: 99%

Differential impact of the ERBB receptors EGFR and ERBB2 on the initiation of precursor lesions of pancreatic ductal adenocarcinoma

Meyers

Gérard

Lemaigre

et al. 2020

Sci Rep

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Earlier diagnosis of pancreatic ductal adenocarcinoma (PDAC) requires better understanding of the mechanisms driving tumorigenesis. In this context, depletion of Epidermal Growth Factor Receptor (EGFR) is known to impair development of PDAC-initiating lesions called acinar-to-ductal metaplasia (ADM) and Pancreatic Intraepithelial Neoplasia (PanIN). In contrast, the role of v-erb-b2 erythroblastic leukemia viral oncogene homolog 2 (ERBB2), the preferred dimerization partner of EGFR, remains poorly understood. Here, using a mouse model with inactivation of Erbb2 in pancreatic acinar cells, we found that Erbb2 is dispensable for inflammation- and KRasG12D-induced development of ADM and PanIN. A mathematical model of EGFR/ERBB2-KRAS signaling, which was calibrated on mouse and human data, supported the observed roles of EGFR and ERBB2. However, this model also predicted that overexpression of ERBB2 stimulates ERBB/KRAS signaling; this prediction was validated experimentally. We conclude that EGFR and ERBB2 differentially impact ERBB signaling during PDAC tumorigenesis, and that the oncogenic potential of ERBB2 is only manifested when it is overexpressed. Therefore, the level of ERBB2, not only its mere presence, needs to be considered when designing therapies targeting ERBB signaling.

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Section: Discussionmentioning

confidence: 99%

Differential impact of the ERBB receptors EGFR and ERBB2 on the initiation of precursor lesions of pancreatic ductal adenocarcinoma

Meyers

Gérard

Lemaigre

et al. 2020

Sci Rep

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show abstract

“…[ 68 ] ERBB2 mutations or amplification were identified in approximately 8.5% pancreatic cancer patients. [ 69 ] Introduction of the ERBB2 mutations into human pancreatic epithelial cells causes oncogenic transformation and increases ERBB2 signaling, anchorage‐independent growth and tumor growth in nude mice, indicating that they are activating mutations. Interestingly, PDACs harboring ERBB2 alternations have concurrence with active KRAS mutations.…”

Section: Targeted Therapies For Pancreatic Cancermentioning

confidence: 99%

Advances in Targeted Therapy and Immunotherapy for Pancreatic Cancer

Liu

Wang

2021

Advanced Biology

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Pancreatic cancer is a highly aggressive malignancy with an overall 5‐year survival rate of <6% due to therapeutic resistance and late‐stage diagnosis. These statistics have not changed despite 50 years of research and therapeutic development. Pancreatic cancer is predicted to become the second leading cause of cancer mortality by the year 2030. Currently, the treatment options for pancreatic cancer are limited. This disease is usually diagnosed at a late stage, which prevents curative surgical resection. Chemotherapy is the most frequently used approach for pancreatic cancer treatment and has limited effects. In many other cancer types, targeted therapy and immunotherapy have made great progress and have been shown to be very promising prospects; these treatments also provide hope for pancreatic cancer. The need for research on targeted therapy and immunotherapy is pressing due to the poor prognosis of pancreatic cancer, and in recent years, there have been some breakthroughs for targeted therapy and immunotherapy in pancreatic cancer. This review summarizes the current preclinical and clinical studies of targeted therapy and immunotherapy for pancreatic cancer and ends by describing the challenges and outlook.

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“…The constructs with RET mutations were confirmed by sequencing. The lentivirus particles containing EV, WT, RET mutants were generated as described [17].…”

Section: Construction Of Mutant Vectors and Packaging Lentivirusmentioning

confidence: 99%

Oncogenic and drug-sensitive RET mutations in human epithelial ovarian cancer

Guan

Xie

et al. 2020

J Exp Clin Cancer Res

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Background: Epithelial ovarian cancer (EOC) is a highly lethal malignancy. Improvement in genetic characterization of EOC patients is required to propose new potential targets, since surgical resection coupled to chemotherapy, presents several limits such as cancer recurrence and drug resistance. Targeted therapies have more efficacy and less toxicity than standard treatments. One of the most relevant cancer-specific actionable targets are protein tyrosine kinases (PTKs) whose role in EOC need to be better investigated. Methods: EOC genomic datasets are retrieved and analyzed. The biological and clinical significance of RET genomic aberrations in ovarian cancer context are investigated by a series of in vitro and in vivo experiments. Results: Epithelial ovarian cancer sequencing projects identify recurrent genomic RET missense mutations in 1.98% of patients, ranking as the top-five hit among the 100 receptor tyrosine kinases-encoding genes. RET mutants R693H and A750T show oncogenic transformation properties in NIH3T3 cells. Introduction of the RET mutants into human EOC cells increases RET signaling, cell viability, anchorage-independent cell growth and tumor xenograft growth in nude mice, demonstrating that they are activating mutations. RET mutants significantly enhance the activation of RET and its downstream MAPK and AKT signaling pathway in ovarian cancer cells. Vandetanib, a clinical approved RET inhibitor, inhibits the cell viability and decreases the activation of RET-MAPK signaling pathways in EOC cells expressing oncogenic RET mutants. Conclusions: The discovery of RET pathogenic variants in the EOC patients, suggests a previously underestimated role for RET in EOC tumorigenesis. The identification of the gain-of-function RET mutations in EOC highlights the potential use of RET in targeted therapy to treat ovarian cancer patients.

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Oncogenic ERBB2 aberrations and KRAS mutations cooperate to promote pancreatic ductal adenocarcinoma progression

Cited by 15 publications

References 49 publications

Differential impact of the ERBB receptors EGFR and ERBB2 on the initiation of precursor lesions of pancreatic ductal adenocarcinoma

Differential impact of the ERBB receptors EGFR and ERBB2 on the initiation of precursor lesions of pancreatic ductal adenocarcinoma

Advances in Targeted Therapy and Immunotherapy for Pancreatic Cancer

Oncogenic and drug-sensitive RET mutations in human epithelial ovarian cancer

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