Release date: 2017-09-29 In 2014, new combination therapies for the treatment of metastatic melanoma entered the market, but after several months of treatment, physicians found that almost all patients who underwent the treatment had a relapse. Why is it recurring? Researchers from the University of Pennsylvania and the Wistar Institute gave answers... Immunofluorescence image of melanoma cells In 2014, a new combination therapy for the treatment of metastatic melanoma entered the market. This treatment helped to prolong the patient's life, but after several months of treatment, the doctors found that almost all patients who underwent the treatment were eventually There is a recurrence. The two FDA-approved drugs were tamifenib as a MEK inhibitor and BRAF inhibitor, respectively, when an open I/II study showed that combination therapy was effective compared to monotherapy. Overall response rate (ORR), but why will it recur afterwards? Recent researchers from the University of Pennsylvania and the Wistar Institute have given some answers: Although combination therapy can block the main pathways by which cancer cells accelerate their growth, cancer cells are smart enough to wrap around a congested road like a vehicle. The lines continue to grow and spread through additional paths. The research was published in the September 28 issue of Nature. One of the co-authors of the article is Wei Guo, a tenured professor of biology at the University of Pennsylvania. He has been involved in the structure and function of extracellular secretory complexes. Related research and efforts to explore the role of this complex in a variety of diseases such as cancer, is a well-known expert in this field. For the latest study, he said, "Tumor cells are smart, and once they are blocked by the first pathway, they activate other pathways, which leads to more invasiveness." First path: BRAF Melanoma is one of the most aggressive skin cancers. In recent years, the number of newly confirmed cases of melanoma in the world has been rising. Like all other cancers, melanoma is caused by abnormal cell accumulation mutations in the body, undergoing transformation, leading to abnormal growth and metastasis. One of the most common mutations in melanoma occurs in the BRAF gene. The study found that about half of metastatic melanoma, an invasive skin cancer that has metastasized to other parts of the body, is caused by a mistake in the cell growth gene BRAF, which encodes a MAPK/ERK pathway. The key enzyme in the signal cascade, if this gene is mutated, then this pathway is over-activated, leading to increased cell growth, which is characteristic of cancer. As a result, scientists have opened RAF inhibitors, hoping to treat these melanomas by targeting this defective gene. This treatment strategy has been very successful, but some patients are unable to respond comprehensively, and those who respond Patients almost inevitably develop resistance. To strengthen the role of BRAF inhibitors, scientists have recently developed a new class of drugs to block enzymes that function downstream of BRAF/MEK: the use of BRAF inhibitors in combination with MEK inhibitors can result in advanced melanoma The patient has passed one of the best treatment options to date. But like BRAF inhibitors, this effect is short-lived. Second day access: PAK A few years ago, Professor Guo Wei and his postdoctoral researcher Hezhe Lu hope to find resistant melanoma cells that are more aggressive than their parents in cell culture assays. To reveal how this resistance develops, they collaborated with Professor Meenhard Herlyn, director of the Wistar Institute's Melanoma Research Center, and another author of the article, to analyze BRAF inhibitor therapy, or BRAF/MEK inhibitors. Cell lines and tumor biopsies of melanoma patients before and after combination therapy. As previously discovered by the study group, they also found that treatment with BRAF inhibitor alone appeared to reactivate ERK downstream of BRAF in the MAPK pathway. But in many cell lines and patient samples that are resistant to combination therapy, the researchers found a difference: ERK was not reactivated, but instead the researchers discovered another parallel pathway: the PAK enzyme pathway was activated. "We found that not only did PAK be activated in many patients, but the downstream targets of PAK were also activated," Professor Guo said. If PAK inhibitors are used to treat cells that are resistant to combination therapy, then the ability of cancer cells to grow can be reduced. And when the researchers added the PAK promoter, they turned on a PAK protein in the metastatic melanoma cell line, and they found that the cells were more resistant to MAPK pathway inhibitors. PAK protein can help melanoma grow rapidly through the action of several different pathways, promote cell cycle progression and inhibit apoptosis. Interestingly, cancer researchers have previously tried to block PAK as a strategy for anti-tumor mechanisms, but found that it does not seem to prevent melanoma progression. "Perhaps only when the ERK pathway is blocked, PAK will become 'awake'. You can see the effect through PAK inhibitors before." "Our findings provide a possible flanking strategy to eliminate the ability of melanoma cells to reconnect their signaling networks," Herlyn said. "When cancer becomes smart, we also need to act smarter." In the future, the research team hopes to use PAK as a complementary tool for targeting melanoma tumors. They are tracking some parallel pathways downstream of PAK, determining how they work, and studying immunotherapy in melanoma treatment. Previously, Professor Guo Wei’s team also found that a protein called Exo70 has a “dividing personality,†a form that allows cells to be under strict control, while another form promotes the ability of the tumor to invade the distal part of the body, thereby Diagnosing the spread of cancer offers new possibilities. Original title PAK signalling drives acquired drug resistance to MAPK inhibitors in BRAF-mutant melanomas Source: Biopass Omega-3 Fish Oil,Fish Oil 10/50 Tg,Omega 3 Fish Oil,10/50 Tg Fish Oil ZHOUSHAN SINOMEGA BIOTECH ENGINEERING CO.,LTD , https://www.sinomegabiotech.com