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  • Targeting the MAPK pathway has attracted significant interes

    2021-07-22

    Targeting the MAPK pathway has attracted significant interest in cancer therapy. Efforts directly targeting RAS protein are believed to be very challenging in spite of the promise shown by a few RAS inhibitors in Desformylflustrabromine hydrochloride mg the early development stage. Clinical benefits achieved by BRAF and MEK inhibitors have shown that targeting these downstream RAS effectors is a very promising approach for therapies of cancers harboring oncogenic mutations in this pathway. However, patients treated with RAF or MEK inhibitors frequently develop drug resistance. The resistance involves very complicated mechanisms, including gene mutations occurring in the targeted proteins, MAPK signaling interaction with PI3K pathway, loss of functions in MAPK signaling feedback control and abnormal alterations of tumor suppressor genes. It has been believed that single drug resistance can trigger multi-drug resistance. Given this situation, researchers continue to pursue approaches that can reverse drug resistance, and develop combinatorial strategies to obtain therapeutic efficacy40, 41.
    Perspective MAPK cascades were discovered more than three decades ago and new functions are continuously revealed50, 55. With the emergence of acquired drug resistance after treatment onset as well as the deeper appreciation that has been obtained in exploration of ERK kinase, there is a growing interest in targeting ERK kinase. The combination usage of ERK inhibitors with upstream inhibition may result in more desirable therapeutic benefits40, 41, 64. It is now clear that combination of different inhibitors of the same target, or drugs for different targets within the same pathway, can result in marked differences in effectiveness compared with single inhibitor, depending on tumor type and mutational status. For example, Moriceau et al. has found that low concentration of ERK alone cannot reverse BRAF-inhibitor and MEK-inhibitor double resistance (DDR, double-drugs-resistance) unless co-targeting BRAF and MEK. High concentration of ERK inhibitors can inhibit the growth of DDR cells, but brings serious adverse effects. Of note, it Desformylflustrabromine hydrochloride mg also has been reported that BRAF inhibitor-resistant melanoma cells also often fail in response to ERK inhibition, which is explained by the ERK-dependent feedback loop to activate RAS and PI3K signaling. This study showed a broader targeting strategy that combining ERK and PI3K/mTOR inhibitors showed sufficient activity in tumors with BRAF inhibitor resistance. Considering the breakthrough of immunotherapy, the combination of inhibition of MAPK kinases and immunotherapy may equip doctors with new weapons in cancer treatment one day. Currently, ERK inhibition is still at its early stage in clinical studies. Clinical studies have not reported the occurrence of acquired resistance to ERK inhibitors. Nevertheless, it is important to note that the possible occurrence of ERK inhibitor resistance caused by ERK1/2 mutation prompts a new question on how to deal with this resistance.
    Introduction Hepatic ischemia/reperfusion (IR) injury, which is characterized by interruption of the hepatic blood supply and subsequent re-establishment of blood flow, is a common consequence of various clinical situations, such as liver transplantation, trauma, shock, and resection of intrahepatic tumors. Hepatic IR can cause graft dysfunction, poor function, or even graft failure after liver transplantation [1,2]. Furthermore, hepatic IR injury also causes injury in the distant organs. For example, acute kidney injury has been observed in rats with hepatic IR injury [3]. Hence, an effective measure against hepatic IR injury is needed. The mechanism of hepatic IR injury is complex, and a variety of factors underlie the mechanism. It has been commonly considered that the hepatic IR injury is triggered by the activation of Kupffer cells. The Kupffer cells are activated, then produce a variety of inflammatory factors, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, interferon (IFN)-γ, and reactive oxygen species (ROS) [4]. Activated Kupffer cells also accumulate and activate neutrophils, thereby aggravating the inflammatory hepatic injury. As a result, proteins involved in cell apoptosis are activated and hepatocytes die during hepatic IR.