Pancreatic ductal adenocarcinoma (PDAC), which accounts for over 90% of pancreatic cancer, is one of the deadliest human malignancies with an overall 5-year survival rate of < 6% due to therapy resistance and late stage at diagnosis. These statistics have not changed despite 50 years of research and therapeutic development. PDAC is predicted to become the second leading cause of cancer mortality by the year 2030. It is usually diagnosed at a late stage which precludes the chance of surgical resection as a cure. Chemotherapy is the most frequently used approach for PDAC treatment with limited effect. Current therapeutic options are thus inadequate, and additional treatments are urgently needed for PDAC patients.    

Recently, Chinese scientists at Shanghai Institute of Nutrition and Health (SINH) of Chinese Academy of Sciences revealed recurrent genomic ERBB2 alterations in PDAC are oncogenic and further found the alterations cooperate with KRAS mutants to promote PDAC progression. The discovery provides new therapeutic target for treating PDAC. 

Biological and functional characterization of cancer genomic alterations has resulted in new therapeutic approaches that have dramatically improved patient outcomes. Mutationally activated oncogenes that promote tumorigenesis represent potential drug targets due to the high dependency of tumor cells on such oncogenes, and mutated receptor tyrosine kinases in particular have been successfully exploited as therapeutic targets in multiple cancers. Examples of this include Gleevec, which targets the KIT oncoprotein in gastrointestinal stromal tumors and Tarceva, an EGFR inhibitor that targets mutant EGFR in lung cancer. In more than 90% of PDAC cases, the key oncogenic driver is an activating KRAS mutation. It occurs as an early genetic event driving pancreatic intraepithelial neoplasia (PanIN; the precursor ductal lesions of PDAC) formation. Additional genetic alterations are required to contribute to the pathogenesis of PDAC.

To better understanding the molecular mechanisms of PDAC progression, a translational research team led by Prof. WANG Yuexiang at SINH reanalyzed the Cancer Genome Atlas (TCGA) PDAC sequencing dataset and other genomic datasets and identified recurrent genomic ERBB2 alterations in PDAC. They further demonstrate that these ERBB2 aberrations are oncogenic, cooperating with KRAS mutants to promote PDAC tumorigenesis. These oncogenic mechanisms can be overcome using ERBB2 inhibitor in combination with KRAS-inhibitory therapy to suppress tumor growth and progression. The intriguing discovery of this ERBB2 oncogenic mechanisms in human PDAC has immediate biologic and therapeutic implications for clinical practice, not only identifying an oncogenic role for ERBB2 aberrations in PDAC tumorigenesis, but also providing a rationale for testing an anti-ERBB2 drug in combination with a KRAS inhibitor in ERBB2-mutant PDAC patients that are currently untreatable. 

A research article describing this work, entitled “Oncogenic ERBB2 Aberrations and KRAS Mutations Cooperate to Promote Pancreatic Ductal Adenocarcinoma Progression” was published online ahead of print in the journal Carcinogenesis on May 2, 2019.  

The research was supported by Prof. SHAO Chenghao at Changzheng Hospital, Prof. LU Yuan at Fudan University and Dr. ZHU li at PLA General Hospital. This study was financially supported by National Natural Science Foundation of China, Ministry of Science and Technology of China, Science and Technology Commission of Shanghai Municipality, and Chinese Academy of Sciences. 

Media Contact:
WANG Jin (Ms.)
Shanghai Institute of Nutrition and Health
Chinese Academy of Sciences
Email: sibssc@sibs.ac.cn