The Latest Research Progress in Cancer Resistance (II)

(Continued)

 

  • Scientific Reports: New Computational Approach to Identify Chemotherapy Targets

 

Global methylation and expression level analysis of CSCs and non-CSCs

(DOI: 10.1038/s41598-018-19284-3)

 

One of the most important features of tumors is the methylation of deoxycytidine to form 5-methylcytosine (5mC). DNA methylation is the process by which a methyl group is added to a DNA molecule.

 

It has been found that the occurrence and distribution of 5mC are important for gene regulation, and it can also serve as a key biomarker for diagnosis. Therefore, the study of the relationship between DNA methylation and transcription is important for revealing cellular responses and the development of new drugs.

 

A large amount of DNA methylation and transcription analysis has produced a large amount of data, but it is difficult to find out the key genes related to cancer development. In order to solve this problem, researchers from Osaka University in Japan used Gaussian equations to convert large amounts of data into smooth functions and extract appropriate information from them—the information that can represent the 5mC methylation level.

 

“Tumors contain cells called cancer stem cells (CSCs), which are self-renewing, carcinogenic, and play an important role in resistance to chemotherapy and radiotherapy.” This study published in the “Science Reports”, the first author Masamitsu Konno explained, “So we wanted to determine the intracellular 5mC by CSC model enzyme ornithine decarboxylase to find therapeutic targets.”

 

A new computational method that integrates gene expression and methylation modification data enabled researchers to successfully discover that TRAF4 is an important chemotherapy resistance gene. In this way, the researchers also determined the effects of several drugs that treat human gastrointestinal cancers, including esophageal cancer. Many studies have reported the abnormal expression of TRAF4 in certain tumors (such as breast, lung, and prostate tumors), but this is the first study to find that TRAF4 is essential for regulating the function of human esophageal cancer CSCs.

 

“Our mathematical approach can simultaneously be used to identify and quantify potential targets for chemoresistance in gastrointestinal cancer stem cells,” said correspondence author Yuichiro Doki. “Our results not only provide key information for drug development targeting esophageal cancer targets, but can also be used for large-scale screening of CSC drug treatment targets.

 

 

  • Nat Commun: Scientists Find Breakthrough in Improving Drug Resistance in Leukemia

 

MPP1 promotes HPC replating and only requires the PDZ domain to bind ABCC4

(DOI: 10.1038/s41467-017-01678-y)

 

Recently, in a study published in Nature Communications, scientists have discovered how the connection between two proteins in acute myeloid leukemia can make tumor cells resistant to chemotherapy, and said that disturbed this connection can make cancer cells more vulnerable to chemotherapy. The study, led by Dr. John Schuetz, Ph.D., Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, will help develop drugs that enhance the efficacy of chemotherapy in patients with acute myeloid leukemia, colon cancer, breast cancer, and medulloblastoma.

 

The development of new therapies for acute myeloid leukemia is critical because the overall 5-year survival rate of this leukemia in adults and children is only 27%. Other scientists have previously found that a protein called ABCC4 has increased significantly in acute myeloid leukemia invasive cases. Based on this research, Schuetz and his colleagues tried to find other proteins that might interact with ABCC4 and make it work. After searching hundreds of candidate proteins, they discovered that a protein called MPP1 was also increased in acute myeloid leukemia.

 

The researchers said that the two proteins are linked to each other and that this connection allows the cells to exhibit the characteristics of highly proliferating leukemia cells. In the experiment, the researchers genetically transformed the blood progenitor cells to possess high levels of MPP1 and ABCC4. The cells grew on the medium and then transferred or reinoculated them into a new medium. Observe whether the cells can continue to grow. This self-renewal is characteristic of leukemia cells. The researchers found that only cells with both high levels of ABCC4 and MPP1 can grow continuously.

 

“Obviously, if you vaccinate normal progenitor cells, you can only succeed once or twice,” Schuetz said. “However, we are very surprised that overexpression of MPP1 – similar to that seen in leukemia – will make the progenitor cells self-renewal, can be re-inoculated again and again, and continue to form new colonies.”

 

This experiment also revealed that these two proteins play a role in the cell membrane, where they can make cancer cells avoid chemotherapy drugs.

 

“When we destroy their interactions, ABCC4 detaches with the cell membrane and cells become more sensitive to leukemia drugs which would have been driven out of cells by ABCC4,” Schuetz said.

 

Through the search for thousands of compounds, the researchers identified those molecules that could disrupt the ABCC4-MPP1 linker. A molecule called antimycin A completely reverses drug resistance in both acute myeloid leukemia cell lines and patient cells. Antimycin A is too toxic to be used in chemotherapy, but the identification of this substance should help scientists find other less toxic drugs to interfere with the ABCC4-MPP1 interaction.

 

This finding can also allow clinicians to identify patients with high levels of ABCC4 and MPP1. Drugs that interfere with ABCC4-MPP1 interactions can amplify the efficacy of chemotherapy, which will benefit these patients, Schuetz said. Similarly, he stated that high levels of ABCC4 and MPP1 are also expressed in other cancers including breast, colon, and medulloblastoma. The chemotherapy efficacy of these cancers will also be enhanced by drugs which interfere with the ABCC4-MPP1 interaction.

 

 

  • Nature: Scientists identify multiple types of resistant cancer cells may have the same hidden weaknesses

 

persister cells have a disabled antioxidant program and depend on GPX4 in vivo

(DOI:10.1038/nature24297)

 

Recently, in a study published in Nature, researchers from the University of California, San Francisco, discovered through research that a particular genetic vulnerability (gene weakness) may help oncologists effectively eliminate a variety types of resistant cancer cells, related research may find new ways for researchers to develop new therapies to inhibit cancer recurrence.

 

Researchers generally believe that the emergence of drug resistance is caused by the genetic evolution of cancer. The cancer cells of some patients will possess or generate some new mutations to promote their survival after resisting the therapeutic effects, resulting in new drug-resistant tumors and recurrence. As early as 2010, researchers from the Massachusetts General Hospital discovered a novel pathway for cancer evasion therapy that does not require new mutations. A portion of persister cells in the tumor will promote tumor cells develop drug tolerance and subsequently induces cancer progression. Dr. Matthew Hangauer said that the key role of these persister cells is currently unknown, but many oncologists will tell you that non-hereditary drug resistance appears to occur in patients and these naturally highly resistant cells may become strong candidates to explain this. In 2016, the researchers found that during cancer therapy, persister cells that can act as tumor remnant cells, can dormant and escape the attack of multiple rounds of therapy. Eventually, some cells will evolve traditional genetic resistance, which leads to recurrence of the disease.

 

To find the biological weaknesses of these persister cells, Hangauer and colleagues used RNA sequencing technology to test untreated breast cancer cell lines and persister cells from these cells (high-dose drug lapatinib survived after 9 days of treatment). The cells were studied to find differences in gene activity between these two types of cells. It was found that persister cells have high gene activity in typical mesenchymal cells, but the activity of some genes responding to oxidative stress is very low.

 

Previously, the researchers found that cancer cells in the interstitial state are very sensitive to the ferroptosis pathway and that they can trigger cell death by blocking glutathione peroxidase 4 (GPX4). In this study, the researchers found that in the laboratory, GPX4 inhibitors can selectively kill drug-treated breast cancer persister cells, while not producing side effect on untreated breast cancer cells or normal breast cells. The researchers then conducted studies on various types of cancers such as melanoma, lung cancer, and ovarian cancer. In each cancer study, they found that GPX4 inhibitors could induce ferroptosis in persister cells treated with drugs, but it has no effect on untreated cancer cells.

 

Hangauer said that GPX4 inhibitors kill persister cells in many types of cancer, and we have now found that the weaknesses of persister cells tolerated to drugs may be beyond the “lineage” of cancer, and that this inhibitor goes beyond the original study, which means that future researchers may develop a universal strategy to eliminate the risk of cancer evasion therapy and recurrence. Researchers believe that combining GPX4 inhibitors with therapies that target tumor shrinkage can effectively eliminate persister cells, which may also be a new strategy for effectively suppressing the recurrence of many types of cancer.

 

In the end, the researchers stated that in the study, they identified a particular genetic susceptibility (gene weakness) shared by many types of resistant cancer cells for the first time. Later, they will develop effective inhibition based on the weakness of the gene, which could even 100% eliminate the recurrence of cancer in patients with new targeted therapy.

 

 

 

Reference

 

Konno M. et al. Computational trans-omics approach characterised methylomic and transcriptomic involvements and identified novel therapeutic targets for chemoresistance in gastrointestinal cancer stem cells. Sci Rep. 2018 Jan 17;8(1):899. doi: 10.1038/s41598-018-19284-3.

 

Pitre A. et al. An unexpected protein interaction promotes drug resistance in leukemia. Nat Commun. 2017 Nov 16;8(1):1547. doi: 10.1038/s41467-017-01678-y.

 

Hangauer MJ. et al. Drug-tolerant persister cancer cells are vulnerable to GPX4 inhibition. Nature. 2017 Nov 9;551(7679):247-250. doi: 10.1038/nature24297. Epub 2017 Nov 1.