Author: Greatly.
Drug resistance is a "stumbling block" that every patient will encounter on the road to anti-cancer, whether it is targeted, immune, or traditional chemotherapy, as long as anti-cancer drugs are used, drug resistance may occur, resulting in disease progression, cancer cells, and metastasis, so that patients have to adjust the plan, increase the cost, and even shorten the survival time.
And a recent study found thatERK5 inhibitors can restore cellular sensitivity to cancer** and address or avoid drug resistanceBringing light to patients!
What is drug resistance?
The problem of drug resistance is the inevitable result of the tumor ** process, and there is no official consensus to classify it clinically, and it is usually divided according to the manifestations of drug resistancePrimary drug resistancewithAcquired drug resistanceTwo categories.
Primary drug resistance refers to the fact that tumor cells are resistant to anticancer drugs at the beginning, resulting in ** failure. Acquired drug resistance refers to the fact that at the beginning, if the cancer cells are sensitive to the drug, a large number of them will be killed, and the remaining cells may be changed in order to escape the killing of the anti-cancer drug, that is, the cancer cells become resistant to the anti-cancer drug.
In anti-cancer**,Chemotherapy, targeted**, and immune** all have the potential to develop drug resistance.
Chemotherapy
Resistance to chemotherapy drugs is a complex issueCancer cells can develop resistance to chemotherapy drugs through a variety of mechanisms, including increasing drug excretion, repairing damaged DNA, altering apoptosis pathways, and developing multidrug resistance.
Targeting**
The mechanism of action of targeted** drugs is to attack specific targets in cancer cellsHowever, if cancer cells have genetic mutations or adaptive changes, they can become resistant to targeted drugs. Common mechanisms of target** resistance include bypass activation, target mutation or amplification, phenotypic transformation, etc.
Immunization**
Immunity** is the attack on cancer cells by activating the patient's own immune system. However, cancer cells can evade immune attack through a variety of mechanisms, allowing them to become resistant to immune**. Common mechanisms of immune** resistance include an increase in immunosuppressive cells or molecules, upregulation of immune checkpoint molecules, genetic mutations, or epigenetic alterations.
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What is an ERK5 inhibitor?
Before talking about ERK5, it is necessary to mention the BRAF mutation in non-small cell lung cancer, I believe you are not unfamiliar with BRAF, BRAF is a serine threonine protein kinase, which belongs to the RAF kinase family. It plays an important role in the MAPK signaling pathway and is closely related to the occurrence and progression of tumors.
ERK5 is a member of the MAPK family and belongs to the MAPK signaling pathway with BRAF. ERK5 Chinese is an extracellular signal-associated kinase 5, also known as MAPK 5, which plays an important role in a variety of signal transduction pathwaysIt is closely related to processes such as the proliferation and survival of cancer cells
According to statistics, the ERK5-editing gene MAPK 7 was amplified in 50% of liver cancer patients, and ERK5 was highly expressed in breast cancer and prostate cancerPatients with high expression have a survival time of 20 months less(34 months vs.)14 months).
At the same time, the results of in vitro experiments show that:ERK5 inhibitors can effectively inhibit the growth and spread of tumor cells。ERK5 inhibitors as:Both monotherapy** and in combination with chemotherapy** have shown efficacy in different cell and tumor models
Therefore, ERK5 inhibitors are considered to be one of the most promising methods in cancer**. At present, there are a number of ERK5 inhibitors in clinical studies in the preclinical and clinical trial stages, including:ax-15836、erk5-in-1Wait.
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How does it solve the problem of drug resistance?
As mentioned above, the ERK5 signaling pathway is one of the important pathways for tumor cell survival, so inhibiting its activation can induce apoptosis in tumor cells. At the same time, ERK5 inhibitors may reduce the resistance of cancer cells to certain drugs and enhance the efficacy of anticancer drugs by regulating the signal transduction pathway of cancer cells and affecting their proliferation and survival.
A recent study by the Autonomous University of Barcelona found that by inhibiting ERK5, it can also restore the sensitivity of tumor cells to fight cancer**, which can be solvedPrimary drug resistance issues, especially in the case of TRAIL agonists**, can improve anti-cancer efficacy.
References.
Tips:
TRAIL agonists are a ** molecule that induces apoptosis by binding to TRAIL receptors on cell membranes, and although they have shown good results in the preclinical stage, they have not been used in clinical trials due to the drug resistance of cancer cells and have not been used in clinical trials.
At the same time, this study was experimented in multiple solid tumor organoids, including lung cancer, endometrial cancer, prostate cancer, cervical cancer, etc., all of which were confirmedERK5 inhibitors can enhance the anti-cancer activity of natural killer (NK) cells。NK cells are a member of the immune system that recognizes and kills abnormal cells, including cancer cells. In other words, the use of ERK5 inhibitors on the basis of anti-cancer** is possibleImproves anti-cancer efficacy, reduces drug resistance, and especially immunity**
Overall, this discovery undoubtedly brings a glimmer of hope to cancer**. If the problem of drug resistance can be solved with ERK5 inhibitors, it means that many cancer patients can continue to use the original regimen, thereby reducing the risk of failure and avoiding unnecessary treatment
At the same time, it can also prolong the survival of patients, improve the quality of life, and enhance the attitude of confidence and positive cooperation. More importantly, it can also accelerate the research and development process of anti-cancer drugs, bringing hope and better results to more cancer patients!
CancerReferences.
1]espinosa-gil, s., ivanova, s., alari-pahissa, e. et al. map kinase erk5 modulates cancer cell sensitivity to extrinsic apoptosis induced by death-receptor agonists. cell death dis 14, 715 (2023).