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KRas induces a Src/PEAK1/ErbB2 kinase amplification loop that drives metastatic growth and therapy resistance in pancreatic cancer.

ABSTRACT: Early biomarkers and effective therapeutic strategies are desperately needed to treat pancreatic ductal adenocarcinoma (PDAC), which has a dismal 5-year patient survival rate. Here, we report that the novel tyrosine kinase PEAK1 is upregulated in human malignancies, including human PDACs and pancreatic intraepithelial neoplasia (PanIN). Oncogenic KRas induced a PEAK1-dependent kinase amplification loop between Src, PEAK1, and ErbB2 to drive PDAC tumor growth and metastasis in vivo. Surprisingly, blockade of ErbB2 expression increased Src-dependent PEAK1 expression, PEAK1-dependent Src activation, and tumor growth in vivo, suggesting a mechanism for the observed resistance of patients with PDACs to therapeutic intervention. Importantly, PEAK1 inactivation sensitized PDAC cells to trastuzumab and gemcitabine therapy. Our findings, therefore, suggest that PEAK1 is a novel biomarker, critical signaling hub, and new therapeutic target in PDACs.

SUBMITTER: Kelber JA

PROVIDER: S-EPMC3366503 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature

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KRas induces a Src/PEAK1/ErbB2 kinase amplification loop that drives metastatic growth and therapy resistance in pancreatic cancer.

Kelber Jonathan A JA Reno Theresa T Kaushal Sharmeela S Metildi Cristina C Wright Tracy T Stoletov Konstantin K Weems Jessica M JM Park Frederick D FD Mose Evangeline E Wang Yingchun Y Hoffman Robert M RM Lowy Andrew M AM Bouvet Michael M Klemke Richard L RL

Cancer research 20120501 10

Early biomarkers and effective therapeutic strategies are desperately needed to treat pancreatic ductal adenocarcinoma (PDAC), which has a dismal 5-year patient survival rate. Here, we report that the novel tyrosine kinase PEAK1 is upregulated in human malignancies, including human PDACs and pancreatic intraepithelial neoplasia (PanIN). Oncogenic KRas induced a PEAK1-dependent kinase amplification loop between Src, PEAK1, and ErbB2 to drive PDAC tumor growth and metastasis in vivo. Surprisingly, ...[more]

PMID: 22589274

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Project description:Pancreatic cancer is a significant cause of cancer-related deaths in Canada. Although it is less common than other cancers, the mortality rate has remained high and stable since 1984, with a five-year net survival rate being the lowest of 23 reported cancers. The limited options for detection and treatment contribute to the high mortality rate. A developing area of treatment is tumour site agnostic targeted therapy, where patients' cancer is treated based on genomic alterations that are amenable to targeted agents, regardless of where the tumour originated. A 52-year-old man with no prior medical history presented with anemia, intermittent fatigue, post-prandial indigestion, and bloating, and 8-10 lbs of unintentional weight loss over a 1-year period. A computed tomography scan of the abdomen revealed pancreatic ductal adenocarcinoma and diffuse liver metastasis. He received multiple local and non-targeted systemic therapies. Serial genomic analyses sequentially revealed c-ros oncogene 1 (ROS1) receptor tyrosine kinase rearrangement, human epidermal growth factor receptor 2 (HER2) amplification, and Kirsten rat sarcoma virus (KRAS) G12C mutation throughout his journey, none of which were present at diagnosis. Each new genomic alteration prompted treatment change. Concurrent with systemic therapy, the patient also received numerous local treatments, including hepatic transarterial chemoembolization, Yttrium 90, Whipple procedure, stereotactic body radiation therapy, and CyberKnife. Over the course of the disease, metastases were found in the lungs, brain, and kidneys. Despite this, the patient had periods of remarkable response and quality of life evidenced by his cycling tour of France. However, nearly five years from diagnosis, the patient elected to pursue supportive care and died from his cancer. This case report demonstrates the importance of repeat genomic analyses in the treatment of advanced cancer and timely access to targeted therapy. The clinical impact of utilizing a tumor-agnostic treatment approach based on these genomic alterations has the potential to yield a strong response both in survival and quality of life.

Dataset Information

KRas induces a Src/PEAK1/ErbB2 kinase amplification loop that drives metastatic growth and therapy resistance in pancreatic cancer.

Publications

KRas induces a Src/PEAK1/ErbB2 kinase amplification loop that drives metastatic growth and therapy resistance in pancreatic cancer.

Similar Datasets

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