Genetic interplay greatly influences drug response of pancreatic cancer patients
Pancreatic cancer is a deadly disease with five-year survival rate around 8-10%. Early detection of pancreatic cancer is difficult, therefore only 20% of patients can receive surgical resection at diagnosis. Gemcitabine-based chemotherapy is the first-line treatment for patients with metastasis, however the response rate is low. So, the survival of pancreatic cancer patients does not improve significantly in the past two decades.
Precision medicine is important for cancer treatment. Pancreatic tumors have different genetic defects and the genetic abnormalities activate signal transduction pathways individually or synergistically, leading to distinct responses of cancer patients to chemotherapy or targeted therapy. How to identify biomarkers to predict drug response via cell-based experiments, animal models and patient genetic testing is a common goal of basic researchers and clinicians. In pancreatic cancer, the most highly mutated genes are K-ras and p53. However, in addition to these two genes, there is often a third genetic hit. The team led by Vice President Wen-Chun Hung of Kaohsiung Medical University found that about 20% of pancreatic cancer patients have genetic defects in the WNT/β-catenin pathway. They established various genetically modified mouse models and showed that mice with a third WNT/β-catenin pathway dysregulation will specifically increase the expression of platelet-derived growth factor (PDGF) compared to those with K-ras and p53 mutations. PDGF produced by cancer cells stimulates the proliferation of pancreatic cancer cells and stellate cells, and promotes the progression and metastasis of pancreatic cancer. In collaborating with National Health Research Institutes and National Cheng Kung University, they also verified the clinical relevance in the blood and tumor tissues of patients with pancreatic cancer. More importantly, through mechanistic study and drug screening, the team demonstrated that the PDGF pathway specifically activates the downstream signaling molecule Src, so mice with K-ras/p53/WNT dysregulations are particularly sensitive to Src inhibitors, suggesting that Src inhibitors may show greater therapeutic benefit on pancreatic cancer patients with specific genetic defects. Also, the blood PDGF content can be used as a biomarker for screening patients. This study establishes novel animal models to explore the genetic interplay on pancreatic tumorigenesis, and identifies a biomarker for selection of patients who may benefit from targeted therapy, the goal of precision medicine. The results have been published in the journal Theranostics.
This article-“Beta-catenin-activated autocrine PDGF/Src signaling is a therapeutic target in pancreatic cancer” , written by Rept. Author Professor Wen-Chun Hung, from Graduate Institute of Medicine, is award for Kaohsiung Medical University 2019 Monthly Excellent Paper Award in Jan.
Paper is available online at https://www.thno.org/v09p0324.htm