CN-122005595-A - Use of a composition of an RB1 gene expression inhibiting substance and an ATR inhibitor

Abstract

The application belongs to the technical field of biological medicines, and particularly relates to application of a composition of a substance for inhibiting RB1 gene expression and an ATR inhibitor. The application discovers that the RB1 gene function deficiency can be used as a biomarker for predicting the sensitivity of tumors to ATR inhibitors, and on the basis, the combination of the RB1 function deficiency and the ATR inhibitors is used for treating cancers, so that a composition of a substance for inhibiting the expression of the RB1 gene and the ATR inhibitors can be used for preparing medicines for treating the cancers.

Inventors

• LOU HUIQIANG
• Hou Wenya
• ZHANG JIAXIN

Assignees

• 深圳大学

Dates

Publication Date

20260512

Application Date

20260121

Claims (10)

1. 1. Use of a combination of a substance that inhibits RB1 gene expression and an ATR inhibitor for the preparation of a medicament for the treatment of cancer.
2. 2. The use of claim 1, wherein the substance that inhibits RB1 gene expression comprises at least one of a substance that knocks down the RB1 gene and a substance that knocks out the RB1 gene; And/or, the ATR inhibitor comprises at least one of Ceralasertib and Berzosertib; And/or the nucleotide sequence of the RB1 gene is shown as SEQ ID No.1, or the amino acid sequence of the protein expressed by the RB1 gene is shown as SEQ ID No. 2.
3. 3. The use of claim 2, wherein knocking down the substance of RB1 gene comprises silencing at least one of miRNA, siRNA, dsRNA, shRNA of the RB1 gene or knocking down the substance of RB1 gene comprises siRNA as shown in SEQ ID No. 3; And/or, the substance that knocks out the RB1 gene includes a CRISPR/Cas9 gene editing system that knocks out the RB1 gene.
4. 4. The use according to any one of claims 1 to 3, wherein the cancer comprises at least one of renal cell carcinoma, cervical cancer, endometrial cancer, ovarian cancer, breast cancer, non-small cell lung cancer, pancreatic cancer, prostate cancer, esophageal gastric cancer, biliary tract cancer, head and neck cancer, bladder cancer, colorectal cancer, glioblastoma, hepatocellular carcinoma; and/or the composition further comprises a DNA damage or replication blocking drug, wherein the DNA damage or replication blocking drug comprises at least one of methotrexate, mercaptopurine, fluorouracil, capecitabine and hydroxyurea.
5. 5. A composition for use in the treatment of cancer comprising a substance that inhibits RB1 gene expression and an ATR inhibitor.
6. 6. The composition of claim 5, wherein the substance that inhibits RB1 gene expression comprises at least one of a substance that knocks down the RB1 gene and a substance that knocks out the RB1 gene; And/or, the ATR inhibitor comprises at least one of Ceralasertib and Berzosertib.
7. 7. The composition of claim 6, wherein the substance that knocks down the RB1 gene comprises at least one of silencing miRNA, siRNA, dsRNA, shRNA of the RB1 gene or the substance that knockdown the RB1 gene comprises an siRNA as shown in SEQ ID No. 3; And/or, the substance that knocks out the RB1 gene includes a CRISPR/Cas9 gene editing system that knocks out the RB1 gene.
8. 8. The composition of any one of claims 5-7, wherein the cancer comprises at least one of renal cell carcinoma, cervical cancer, endometrial cancer, ovarian cancer, breast cancer, non-small cell lung cancer, pancreatic cancer, prostate cancer, esophageal gastric cancer, biliary tract cancer, head and neck cancer, bladder cancer, colorectal cancer, glioblastoma, hepatocellular carcinoma; and/or the composition further comprises a DNA damage or replication blocking drug, wherein the DNA damage or replication blocking drug comprises at least one of methotrexate, mercaptopurine, fluorouracil, capecitabine and hydroxyurea.
9. 9. Use of ATR inhibitor for the manufacture of a medicament for the treatment of cancer with deleted RB1 gene function.
10. 10. The use of claim 9, wherein the ATR inhibitor comprises at least one of Ceralasertib and Berzosertib; And/or the cancer with the RB1 gene function deficiency comprises at least one of renal cell carcinoma, cervical cancer, endometrial cancer, ovarian cancer, breast cancer, non-small cell lung cancer, pancreatic cancer, prostate cancer, esophageal gastric cancer, biliary tract cancer, head and neck cancer, bladder cancer, colorectal cancer, glioblastoma, hepatocellular carcinoma; And/or the ATR inhibitor and a DNA damage or replication blocking medicament are combined for use, wherein the DNA damage or replication blocking medicament comprises at least one of methotrexate, mercaptopurine, fluorouracil, capecitabine and hydroxyurea.

Description

Use of a composition of an RB1 gene expression inhibiting substance and an ATR inhibitor Technical Field The application belongs to the technical field of biological medicines, and particularly relates to application of a composition of a substance for inhibiting RB1 gene expression and an ATR inhibitor. Background Precise regulation of the cell cycle is critical to maintaining genomic stability and preventing tumorigenesis. Retinoblastoma protein (Retinoblastoma-associated protein, abbreviated as RB or RB 1) is a protein encoded by the RB1 gene, is a core regulator of the G1/S phase checkpoint of the cell cycle, and inhibits the progression of the cell cycle by inhibiting the activity of E2F transcription factors. In most human cancers, there is functional inactivation of the RB pathway (e.g., CDK4/6-cyclin D-RB-E2F), leading to deregulated cell cycle and unlimited proliferation. Currently, inhibitors of CDK4/6 (e.g. Palbociclib) targeting upstream of this pathway have been clinically successful, but their efficacy is dependent on the intact RB1 gene and is ineffective in RB 1-deleted tumors. The DNA-damage response (DDR) pathway is another core mechanism of cells to cope with replication stress and DNA damage. ATR kinase (Ataxia TELANGIECTASIA AND RAD-RELATED KINASE) is a key sensor of the DDR pathway, particularly playing a central role in coping with replication stress. Inhibitors of ATR kinase (ATR inhibitor, ATRi) can disrupt the DDR capacity of cancer cells, leading to DNA damage accumulation and cell death. However, ATR inhibitors have limited efficacy in many solid tumors when used as single agents, and their efficacy prediction biomarkers are ambiguous, limiting the accuracy of their clinical application. Disclosure of Invention The application aims to provide application of a composition of a substance for inhibiting RB1 gene expression and an ATR inhibitor, and aims to solve the technical problem of how to form a novel combination strategy for better treating tumors. In order to achieve the purposes of the application, the technical scheme adopted by the application is as follows: In a first aspect, the present application provides the use of a composition of a substance that inhibits RB1 gene expression and an ATR inhibitor in the manufacture of a medicament for the treatment of cancer. In some embodiments, the substance that inhibits RB1 gene expression comprises at least one of a substance that knocks down the RB1 gene and a substance that knocks out the RB1 gene; And/or, the ATR inhibitor comprises at least one of Ceralasertib and Berzosertib; And/or the nucleotide sequence of the RB1 gene is shown as SEQ ID No.1, or the amino acid sequence of the protein expressed by the RB1 gene is shown as SEQ ID No. 2. In some embodiments, the substance that knocks down the RB1 gene comprises at least one of silencing miRNA, siRNA, dsRNA, shRNA of the RB1 gene, or the substance that knocks down the RB1 gene comprises an siRNA as shown in SEQ ID No. 3; And/or, the substance that knocks out the RB1 gene includes a CRISPR/Cas9 gene editing system that knocks out the RB1 gene. In some embodiments, the cancer comprises at least one of renal cell carcinoma, cervical cancer, endometrial cancer, ovarian cancer, breast cancer, non-small cell lung cancer, pancreatic cancer, prostate cancer, esophageal gastric cancer, biliary tract cancer, head and neck cancer, bladder cancer, colorectal cancer, glioblastoma, hepatocellular carcinoma; and/or the composition further comprises a DNA damage or replication blocking drug, wherein the DNA damage or replication blocking drug comprises at least one of methotrexate, mercaptopurine, fluorouracil, capecitabine and hydroxyurea. In a second aspect, the application provides a composition for treating cancer comprising a substance that inhibits RB1 gene expression and an ATR inhibitor. In some embodiments, the substance that inhibits RB1 gene expression comprises at least one of a substance that knocks down the RB1 gene and a substance that knocks out the RB1 gene; And/or, the ATR inhibitor comprises at least one of Ceralasertib and Berzosertib. In some embodiments, the knocking down the RB1 gene comprises silencing at least one of miRNA, siRNA, dsRNA, shRNA of the RB1 gene, or the knocking down the RB1 gene comprises an siRNA as shown in SEQ ID No. 3; And/or, the substance that knocks out the RB1 gene includes a CRISPR/Cas9 gene editing system that knocks out the RB1 gene. In some embodiments, the cancer comprises at least one of renal cell carcinoma, cervical cancer, endometrial cancer, ovarian cancer, breast cancer, non-small cell lung cancer, pancreatic cancer, prostate cancer, esophageal gastric cancer, biliary tract cancer, head and neck cancer, bladder cancer, colorectal cancer, glioblastoma, hepatocellular carcinoma; and/or the composition further comprises a DNA damage or replication blocking drug, wherein the DNA damage or replication blocking drug comprises at least on