"Mr. Critical" for Imatinib resistance has been found

CDK1 is the offensive weakness of imatinib-resistant gastrointestinal stromal tumors (GIST).

Although there are follow-up treatment options after imatinib resistance, such as second-line sunitinib and third-line regorafenib, the treatment effect is not ideal, and some side effects are even obvious.

Obviously, this work is urgent, especially doctors, patients and their families are looking forward to a more effective treatment plan for imatinib-resistant gastrointestinal stromal tumors.

Therefore, from the perspective of functional genomics, Wang Yuexiang’s research team proved for the first time that CDK1 is the offensive weakness of imatinib-resistant gastrointestinal stromal tumors, and clarified the new functions and substrates of CDK1 outside the cell cycle, and proposed CDK1 drive The treatment strategy of gastrointestinal stromal tumors provides new strategies and preclinical experimental data for overcoming imatinib resistance.

The pain of imatinib resistance

Gastrointestinal stromal tumor is the most common tumor in the gastrointestinal tract, which can occur in any part of the gastrointestinal tract, 60% of which occur in the stomach and 30% in the small intestine.

For patients with gastrointestinal stromal tumors, 2002 is a particularly important time point.

Imatinib is also regarded as a major breakthrough "from 0 to 1.

The advent of imatinib benefited from the significant progress made in the study of gastrointestinal stromal tumors in 1998.

A reporter from China Science News learned that the main cause of death of gastrointestinal stromal tumors is tumor recurrence and metastasis.

"Imatinib is also used in preoperative adjuvant therapy to shrink tumor cells for subsequent surgical treatment.

Although imatinib can provide nearly 3 years of tumor control for about 80% of patients with unresectable or metastatic gastrointestinal stromal tumors, studies have found that about 80% of patients will develop secondary drug resistance within 2 years.

"Once a patient with gastrointestinal stromal tumor develops drug resistance, it is easy to cause multiple drug resistance, that is, tumors that have metastasized to different parts of the body will develop drug resistance.

When imatinib is resistant, the commonly used targeted therapies are second-line sunitinib, third-line recafenib, etc.

The root of the problem also returns to the imatinib-resistant gastrointestinal stromal tumor itself.

Interesting "No.

It is not only Wang Yuexiang's research group studying imatinib-resistant gastrointestinal stromal tumors.
This problem is a recognized hotspot and difficult problem in the field of basic and clinical research on stromal tumors.

"But previous research tended to start from the perspective of structural genomics.
We changed a strategy and started from the perspective of functional genomics.
" Wang Yuexiang told the China Science Daily that the former is aimed at whole-genome sequencing, while the latter is through Identify the role of a gene in a biological model to understand the function of a newly discovered gene.

Therefore, Wang Yuexiang’s research team established a series of kinase inhibitor-sensitive/resistant gastrointestinal stromal tumor models based on the occurrence characteristics of imatinib-resistant gastrointestinal stromal tumors, and screened imatinib-resistant tumors through a genome-wide system.
Potential offensive weakness of drug gastrointestinal stromal tumors.

When the second of the top 2 of all essential genes was screened, the researchers were very happy.

"Analyzed by multi-omics sequencing data analysis of advanced and early gastrointestinal stromal tumors, CDK1 was found to be highly expressed in about 30% of advanced gastrointestinal stromal tumors in 3 Chinese gastrointestinal stromal tumors, and almost in early GIST.
No expression.
" Lu Xiaojing, the first author of the paper and a doctoral student in Wang Yuexiang's research group, told China Science Daily.

"The shortcoming of this research is that only about 30% of advanced gastrointestinal stromal tumors are found, and 70% are not found.
" Wang Yuexiang admitted.
Therefore, the research group is using the latest methods to find the other 70%.

If CDK1, which is ranked 2nd, has a good effect, wouldn’t it be more important for the 1st gene?

"It is indeed important.
" Wang Yuexiang explained to reporters, but there is no corresponding targeted drug for this gene at present, "let it go for now.
"

The more researched, the more interesting.
Wang Yuexiang’s research team carried out in vivo and in vitro functional experiments on CDK1, which further proved that gastrointestinal stromal tumors with high CDK1 expression are CDK1-dependent.
Knockout of CDK1 inhibits cell growth and tumor formation in vivo and in vitro, and promotes cell apoptosis.
And aging.

In this way, the "Mr.
Key" of imatinib-resistant gastrointestinal stromal tumors proved to be CDK1.

Wang Yuexiang and members of the research team observed the results of the experiment.

Old protein still has new functions

CDK1 protein is not a new protein.
It is often recognized that it has the function of regulating the cell cycle like other CDK proteins.
However, as research continues to deepen, more new functions outside the cell cycle of CDK1 have been discovered.
For example, it has recently been discovered that CDK1 regulates epigenetic regulators and maintains specific epigenetic characteristics in stem cells.

Wang Yuexiang does not deny the function of CDK1 in regulating the cell cycle, "but in gastrointestinal stromal tumors, it does not act by regulating the cell cycle.
"

Wang Yuexiang's research group further studied CDK1 and made new discoveries.

"The kinase CDK1 directly binds to its substrate AKT and phosphorylates serine 473 and tyrosine 308, thereby promoting the proliferation and progression of gastrointestinal stromal tumors.
" Wang Yuexiang told the Chinese Journal of Science that this molecular mechanism explains the advanced stomach Causes of AKT hyperphosphorylation in intestinal stromal tumors.

Although knocking out CDK1 can promote cell apoptosis and senescence, this is not a currently feasible treatment method, nor is it the original intention of Wang Yuexiang's group to continue to study CDK1.

As a result, the research group studied the small molecule inhibitor of CDK1, RO-3306.
The results of the study prove that the small molecule inhibitor significantly inhibits cell proliferation in gastrointestinal stromal tumors with high CDK1 expression, but has no effect on gastrointestinal stromal tumor cells that do not express CDK1.

"In animal models, CDK1 inhibitors significantly inhibited tumor growth, proving that CDK1 inhibitors have anti-imatinib-resistant gastrointestinal stromal tumor activity.
" Wang Yuexiang said.
And such results provide new strategies and preclinical experimental data for overcoming imatinib resistance.

"In this study, the experimental design is very convincing in terms of mechanism research and functional exploration," said Gao Jing, a researcher at the Shenzhen Hospital of Cancer Hospital of the Chinese Academy of Medical Sciences.
However, in the era of precision treatment, if CDK1 inhibitors are used to carry out In clinical research, can CDK1 expression be used for patient screening and what are the screening criteria? Is there any change in CDK1 expression before and after imatinib resistance?

These are also issues that Wang Yuexiang's research group needs to continue to tackle.
At the same time, the research group also wants to know a series of scientific issues such as how gastrointestinal stromal tumors form and when they will grow up and progress.
It is reported that Wang Yuexiang led the research team to do this work at the same time.
(Source: Qin Zhiwei, China Science News)

Related paper information: org/10.
1158/0008-5472.
CAN-20-3580" target="_blank">https://doi.
org/10.
1158/0008-5472.
CAN-20-3580