Mol Cancer Res: overcome the drug resistance of pancreatic cancer, and the combination of new drugs makes the king of cancer bow his head and admit defeat

August 23, 2019 / bioin / - pancreatic cancer is one of the most deadly cancers Once the disease spreads, the average survival of patients is less than one year, and there is an urgent need to evaluate more treatment targets The chemotherapy drug abemaciclib is effective in the treatment of breast cancer, but there is little pre clinical evaluation of the drug targeting the treatment of pancreatic cancer A new study by the Sidney Kimmel Cancer Center Jefferson health (skcc) provides evidence to support the use of abemaciclib in pancreatic cancer, and proposes new goals to improve the efficacy of the drug and break the common drug resistance problems in the disease The study was recently published in the journal Molecular Cancer Research "We don't know how abemaciclib works against pancreatic cancer, or how it can be used in combination with other drugs to improve its efficacy "Said Jonathan Brody, research director, Department of surgery, Thomas Jefferson University, CO leader of the skcc gastrointestinal cancer project and senior author of the study Photo source: molecular cancer research to study the mechanism of action of the drug, the researchers evaluated the role of abemaciclib in pancreatic ductal adenocarcinoma cell line They found that the drug can cause cell death and prevent cell growth Compared with the control group, the tumor growth rate of mice treated with drugs decreased Abemaciclib targets enzymes that regulate cell division However, these enzymes only work when combined with another group of enzymes "So we think that pairing abemaciclib with another drug, targeting two groups of enzymes, could have synergistic antitumor effects," explains Christopher Schultz, a doctoral student at Thomas Jefferson University In fact, the current standard of pancreatic care usually uses a combination of multiple chemotherapy drugs The team screened potential therapeutic drugs that could be used in combination with abemaciclib and found that inhibitors of the two proteins, HuR and Yap1, had a synergistic inhibitory effect on cancer growth They confirmed their hypothesis by treating cancer cells with abemaciclib or abemaciclib alone plus other potential anticancer drugs (inhibitors of HuR or Yap1) They found that combination therapy was 2-4 times more effective in inhibiting cell viability Drug resistance is an important issue in the treatment of cancer, which means that cancer cells are less sensitive to chemotherapy drugs after long-term exposure The researchers mimicked chronic therapy by treating cells with abemaciclib for 10-12 months, when the cells were four times more resistant to abemaciclib When these cells come into contact with common therapeutic drugs like gemcitabine, they do not respond to the treatment However, abemaciclib resistant cells are still sensitive to the inhibitors of HuR or Yap1 These findings provide the basis for the further study of the characteristics of abemaciclib and for the future clinical trials In addition, this study for the first time showed the synergistic effect between abemaciclib and Hur / Yap1 inhibitors in vitro Further research on this in vivo combination therapy is under way Dr Brody said: "there are already inhibitors of HuR and Yap1 that have played a role in the body, but there is no clinical application at present We are working on the development of a HuR inhibitor that is expected to be used in clinical trials at the University of Jefferson "The outstanding work done by Dr Brody and his team highlights the vision of Sidney Kimmel Cancer Center to promote the scientific discovery of possible clinical transformation and provide better treatment options for patients with pancreatic cancer, which is usually a fatal disease, for which effective treatment is very necessary "Said WM Kevin Kelly, director of solid tumor oncology and deputy director of clinical research at skcc "These findings may help to design new targeted treatment combinations for pancreatic cancer, which will help overcome the drug resistance of these tumors "Reference: Teena Dhir et al, abemaciclib is effective against pancreatic cancer cells and synchronizes with ur and Yap1 initiation, molecular cancer research (2019) Doi: 10.1158/1541-7786.mcr-19-0589