[Nature sub-issue] Too cunning, "anti-cancer magic drug" PARP inhibitor can also allow cancer cells to escape! Research reveals the secret of how cancer cells resist targeted therapy

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Author: Daisy Introduction: PARP inhibitor is a medical agent that can affect the way of self-replication of cancer cells.
It can treat hereditary cancers with the same "rogue genes" such as ovarian cancer, prostate cancer and pancreatic cancer, and is known as a "universal weapon" against various cancers
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But PARP inhibitors don't work for everyone.
Recently, researchers published a new study in Nature Cell Biology that used cell line and protein analysis techniques to find out how cancer cells develop drug resistance
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They found that blocking p97 made cancer cells more vulnerable to PARP inhibitors -- suggesting a potential way to address treatment resistance
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Also, when disulfiram, which is used to treat alcohol addiction, is used in combination with a PARP inhibitor, the therapeutic effect can be enhanced
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Understanding the mechanisms behind drug resistance can make existing drugs better available to more people
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Scientists have revealed how cancer resists PARP inhibitors, a type of precision medicine used to treat thousands of patients around the world
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Scientists at Newcastle University in the UK call it: a drug for breast cancer can be transformed into a "universal weapon" against all types of cancer
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Their research found that some cancer cells can escape the effects of PARP inhibitors by removing the PARP protein attached to their DNA
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The researchers believe that existing drugs—including those used to treat alcohol addiction—may make PARP inhibitors more effective by preventing cancer cells from removing PARP
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In the future, the findings could also help predict which patients are more likely to respond to PARP inhibitors
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The research, led by scientists at the Institute of Cancer Research, London, published in the journal Nature Cell Biology, was funded by Cancer Research UK with additional support from Breast Cancer Now
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The researchers published an article titled "The ubiquitin-dependent ATPase p97 removes cytotoxic trapped PARP1 from chromatin": https:// PARP inhibitors including olaparib (Olaparib) PARP inhibitors, including laparib) and rucaparib (rucaparib), are used to treat some patients with ovarian, breast, prostate, and pancreatic cancers—usually those who inherit a defective BRCA1 or patients with the BRCA2 gene
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To date, more than 30,000 patients worldwide have been treated with olaparib
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PARP inhibitors target PARP1, which is a DNA repair tool - inactivating it and locking it onto DNA
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Not only does this prevent DNA repair, but the trapping of PARP1 on DNA can eventually cause cancer cells to die
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But PARP inhibitors are not effective for everyone, and it is estimated that more than 40 percent of patients with defective BRCA1 or BRCA2 genes do not respond to them
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To better understand this, Professor Chris Lord and his team from the Institute of Cancer Research (ICR) used cell line and protein profiling techniques to find out how cancer cells develop drug resistance
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The role of p97 They looked for proteins that attach to PARP1 only when it is captured, which may play a role in separating it from DNA
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The research team found that a small molecule called p97 plays a key role in the process of obtaining PARP1 from DNA, saving cancer cells from destruction
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The researchers wondered what would happen if this last stage was blocked
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They used human "organoids," miniature tumors constructed from tissue from triple-negative breast cancer patients and patients with BRCA1 mutations; people who may be eligible for treatment with PARP inhibitors
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Blocking p97 made cancer cells more vulnerable to the PARP inhibitor talazoparib (talazoparib), suggesting a potential pathway to address treatment resistance
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For example, a 1nM dose of talazoparib killed about 30 percent of cancerous organoids, but when combined with a p97 inhibitor called disulfiram (disulfiram), that number reached 90 percent
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This finding suggests that disulfiram, commonly used to treat alcohol addicts, could be used in combination with PARP inhibitors to improve the chances of successful treatment
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For Professor Lord and his team, the next challenge was to translate their new understanding of PARP inhibitor resistance into a method to predict which patients should be treated with PARP inhibitors, and who would be better suited to receive different cancer treatment
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Adapting Therapeutics Professor Chris Lord, Professor of Cancer Genomics, Institute for Cancer Research, London, said: "PARP inhibitors are the most exciting class of drugs in precision cancer treatment today, but we are only now more fully understanding why they are effective in some patients.
, and was not effective in other patients
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" "Now that we have discovered the role of p97 in controlling resistance to PARP inhibitors, we can provide treatments that could save more lives in the future
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" "We believe that our findings will lead to Helps us predict which patients should receive a PARP inhibitor, which patients may need a PARP inhibitor in combination with other drugs to have the best chance of successful treatment, or which patients might be better off on a completely different treatment
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" Mechanism UK's chief executive Michelle Mitchell said: "Our scientists helped discover the BRCA gene 25 years ago
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Now we have drugs that target this mutation and it has saved a lot of lives
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"But we know that , cancer can rapidly outpace the best treatments
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It is important to understand the mechanisms behind drug resistance so we can make existing drugs better for more people
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" "New combinations using existing drugs are A smart way to stay one step ahead of cancer, we will need more research to understand the effectiveness of this approach against PARP inhibitors
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But the findings of this study are a promising new approach by providing patients with the most effective treatment to increase the patient's chances
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"We hope this research will lead to new treatment options," said Dr Simon Vincent, director of research at Breast Cancer Now.
"People who have inherited the genetic mutation have a higher risk of developing breast cancer, with thousands of BRCA1 cases in the UK every year.
" Or people with mutations in the BRCA2 gene have been diagnosed with the disease
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"PARP inhibitor drugs work well against cancer cells with mutations in the BRCA gene, however, they don't work for everyone, and some cancers develop resistance to this targeted therapy, so we continue to fund research to understand resistance.
" Medicinal properties are important
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Excitingly, this study shows that drugs currently used to treat alcohol addiction can be combined with PARP inhibitors to make the treatment of breast cancer caused by a mutated BRCA gene more effective
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We hope this research will lead to new treatment options and better ways to tailor treatment to each patient so that each person receives the treatment that works best for them
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"This breakthrough is the result of tireless work by world-class researchers, including many UK researchers who fund Breast Cancer Now, who have helped develop PARP inhibitor drugs over the past 20 years and laid the groundwork for this promising discovery
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Reference: https://medicalxpress.
com/news/2022-01-uncovers-cancers-resist-treatment.
html Note: This article is intended to introduce the progress of medical research and cannot be used as a reference for treatment plans
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