Use of a polypeptide in combination with a PARP inhibitor for the manufacture of a medicament for the treatment of breast cancer

Abstract

The application discloses application of a polypeptide and a PARP inhibitor to preparation of a drug for treating breast cancer, wherein the sequence of the polypeptide is shown as SEQ ID NO:1, and the PARP inhibitor is olaparib or talazoparib. The polypeptide can down-regulate expression of a DNA damage repair gene FANCD2 protein and block DNA interchain cross-link damage repair. The PARP inhibitor blocks DNA single strand break damage repair by inhibiting catalytic activity of PARP and is mainly used for breast cancer treatment of BRCA mutation. The polypeptide and the PARP inhibitor jointly destroy a cell replication fork protection mechanism caused by DNA damage in two different ways, so that DNA replication forks of breast cancer cells are prone to arrest and collapse, thereby causing cell death. The application shows synergistic anticancer activity in BRCA wild type and BRCA mutant breast cancer subtypes, and is expected to provide a new treatment strategy for clinical treatment of breast cancer.

Description

Technical Field

[0001] This invention relates to the field of antitumor drugs, and more particularly to the application of a polypeptide and PARP inhibitor composition in the preparation of drugs for treating breast cancer. Background Technology

[0002] Breast cancer is one of the most common malignant tumors among women worldwide and a leading cause of cancer death in women, placing a heavy burden on public health. Current clinical treatments for breast cancer primarily involve surgery, radiotherapy, chemotherapy, and endocrine therapy. However, traditional treatments, such as chemotherapy, have significant side effects, easily induce drug resistance, and lead to decreased efficacy. Furthermore, different subtypes of breast cancer exhibit considerable differences in their sensitivity to chemotherapy drugs. Peptide drugs, with their high specificity, low toxicity, and good biocompatibility, can improve anti-tumor efficacy by targeting breast cancer-related molecules or key signaling pathways, and hold promise for reducing the adverse reactions and drug resistance risks associated with traditional treatments.

[0003] The SND1-MTDH tumor protein complex, which targets the staphylococcal nuclease and tudor domain containing 1 (SND1) and metadherin (MTDH), is a key oncogenic target in the occurrence and progression of breast cancer. The binding of SND1 to MTDH can promote breast cancer cell proliferation, survival, and metastasis, and maintain a tumor stem cell population, thereby accelerating tumor progression and malignant transformation. Simultaneously, the SND1-MTDH complex can also weaken tumor antigen presentation and inhibit anti-tumor immune responses. However, whether inhibitors targeting SND1-MTDH can sensitize breast cancer chemotherapy drugs and their clinical application prospects remain unclear.

[0004] FANCD2 (Fanconi anemia complement D2), a DNA damage repair gene, is a key gene that helps tumor cells repair interstrand cross-link damage. It assists damaged DNA in restoring its normal structure, thereby ensuring smooth DNA replication and maintaining genomic stability, allowing tumor cells to proliferate continuously and develop drug resistance. SND1-MTDH inhibitors can downregulate the expression of FANCD2 protein, blocking the repair of DNA interstrand cross-link damage.

[0005] PARP (polyadenosine diphosphate ribose polymerase) is a key enzyme involved in DNA damage repair and maintaining genome stability. After DNA damage occurs in tumor cells, PARP catalyzes the formation of poly(ADP-ribose) chains, thereby recruiting various DNA repair proteins to repair single-strand breaks. Clinically, PARP inhibitors are mainly used for the precision treatment of HER2-negative breast cancer carrying mutations in the germline breast cancer susceptibility gene (BRCA). Olaparib and tapolazoparib are currently the main PARP inhibitors used clinically. PARP inhibitors are insensitive to BRCA wild-type breast cancer. For BRCA-mutated breast cancer, with prolonged administration, breast cancer cells can acquire resistance through various mechanisms such as BRCA reverse mutation and DNA repair pathway reactivation. This has become one of the main challenges in PARP inhibitor treatment of breast cancer; therefore, it is urgent to further optimize treatment regimens through combination therapy and other strategies. Summary of the Invention

[0006] To address the shortcomings of existing clinical drug treatments for breast cancer patients, this invention proposes a novel combination drug therapy strategy for breast cancer. A peptide targeting the SND1-MTDH complex, combined with a PARP inhibitor, synergistically blocks the repair of DNA cross-linking damage and single-strand break damage in breast cancer cells. These two different mechanisms of DNA damage jointly disrupt the cell's replication fork protection mechanism, making the DNA replication forks in breast cancer cells prone to arrest and collapse, thereby leading to cancer cell death. This drug combination exhibits synergistic anti-tumor activity in both BRCA wild-type and BRCA-mutated breast cancer subtypes.

[0007] To solve the above-mentioned technical problems, the technical solution of the present invention is as follows: the application of a composition of a polypeptide and a PARP inhibitor in the preparation of a drug for treating breast cancer, wherein the polypeptide is a polypeptide targeting the SND1-MTDH complex, and its amino acid sequence is shown in SEQ ID NO: 1.

[0008] Preferably, the last amino acid Trp in the polypeptide sequence is protected with an amino group.

[0009] Preferably, the PARP inhibitor is one or both of olaparib and talazoparib.

[0010] Preferably, the PARP inhibitor is olaparib or a pharmaceutically acceptable salt thereof.

[0011] Preferably, the PARP inhibitor is tapolaparib or a pharmaceutically acceptable salt thereof.

[0012] Olaparib and talazoparib are primarily used in existing regimens for the treatment of breast cancer with BRCA (Breast Cancer Susceptibility Gene) mutations. This drug combination has demonstrated synergistic anti-tumor activity in both BRCA wild-type and BRCA-mutated breast cancer subtypes.

[0013] Preferably, the mass ratio of the polypeptide to the PARP inhibitor is 1:10 to 10:1, and more preferably 1:5 to 5:1.

[0014] Preferably, the breast cancer is basal-like triple-negative breast cancer, including BRCA wild-type breast cancer subtypes or BRCA-mutated breast cancer. More preferably, the breast cancer is BRCA wild-type triple-negative breast cancer.

[0015] The key features of this invention are: This invention discloses for the first time a novel drug regimen combining a peptide targeting the SND1-MTDH tumor protein complex with a PARP inhibitor for the treatment of breast cancer. The amino acid sequence of the peptide is shown in SEQ ID NO: 1. This peptide is an inhibitor that specifically targets and blocks the SND1-MTDH complex. It downregulates the expression of FANCD2, a DNA interstrand crosslinking damage repair protein, significantly inhibiting breast cancer cell growth and inducing DNA damage and apoptosis. The PARP inhibitors olaparib and tapolaparib are small molecule compounds that inhibit PARP-mediated DNA single-strand break repair, leading to DNA damage accumulation and triggering breast cancer cell apoptosis. Clinical use of PARP inhibitors in breast cancer is currently limited to BRCA gene-mutated subtypes, with poor sensitivity to BRCA wild-type subtypes. The combination drug strategy of this invention can enhance the efficacy of PARP inhibitors. This enhancement is effective against both BRCA-mutated and BRCA wild-type subtypes, thus expanding the clinical application scope of PARP inhibitors.

[0016] It is noteworthy that this invention has discovered that the synergistic effect of the peptide with the PARP inhibitor is specific. To verify this, this invention compared the combined effect of the peptide with another CDK4 / 6 inhibitor commonly used in breast cancer treatment (Ribocib) (see Example 2). The results showed that the two only had an additive effect, without any synergistic effect. This further demonstrates that the synergistic mechanism of the composition of this invention based on the complementarity of DNA damage repair pathways is unique.

[0017] Compared with existing technologies, this invention has the following advantages: This invention is the first to propose a strategy of combining a peptide inhibitor targeting the SND1-MTDH complex with a PARP inhibitor for the treatment of breast cancer. By simultaneously targeting two DNA repair pathways, a synergistic anti-tumor effect is achieved. This drug combination has shown significant synergistic tumor-suppressive activity in both BRCA wild-type and BRCA-mutated breast cancer cells, potentially overcoming the limitation of PARP inhibitors to treating BRCA-mutated breast cancer and the drug resistance problem caused by long-term monotherapy with PARP inhibitors, thereby expanding the applicability of PARP inhibitors in the clinical treatment of breast cancer. Attached Figure Description

[0018] Figure 1 The results show the synergistic inhibition of triple-negative breast cancer cell proliferation by the combination of peptide and PARP inhibitor olaparib. A and B are the dose-response matrix heatmap and the Highest Single Agent (HSA) synergistic effect score of the combination of peptide and olaparib in triple-negative breast cancer cells MDA-MB-231, respectively. C and D are the dose-response matrix heatmap and the Highest Single Agent (HSA) synergistic effect score of the combination of peptide and olaparib in triple-negative breast cancer cells HCC1937, respectively. Figure 2 The results show the synergistic inhibition of triple-negative breast cancer proliferation by the combination of peptide and PARP inhibitor tprazole. A and B are the dose-response matrix heatmap and the Highest Single Agent (HSA) synergistic effect score of the combination of peptide and tprazole in triple-negative breast cancer cells MDA-MB-231, respectively. C and D are the dose-response matrix heatmap and the Highest Single Agent (HSA) synergistic effect score of the combination of peptide and tprazole in triple-negative breast cancer cells HCC1937, respectively. Figure 3 The results show the synergistic inhibition of triple-negative breast cancer proliferation by the combination of the peptide and ribociclib, an inhibitor of CDK4 / 6, in the treatment of breast cancer. A and B are the dose-response matrix heatmaps and the Highest Single Agent (HSA) synergistic effect scores of the combination of the peptide and ribociclib in triple-negative breast cancer cells MDA-MB-231. C and D are the dose-response matrix heatmaps and the Highest Single Agent (HSA) synergistic effect scores of the combination of the peptide and ribociclib in triple-negative breast cancer cells HCC1937. Figure 4The effects of the present invention's peptide on the expression of the DNA damage repair protein FANCD2 are shown in Figure A; Figure B shows the dose-dependent downregulation of FANCD2 protein expression by the peptide in combination with the PARP inhibitor olaparib. Figure 5 The present invention describes the inhibitory effects of the peptide combined with olaparib on cellular DNA damage and growth; A shows the peptide combined with the PARP inhibitor olaparib inducing DNA damage in MDA-MB-231 cells and inhibiting cell growth; B shows the peptide combined with olaparib inducing DNA damage in HCC1937 cells and inhibiting cell growth. Figure 6 The results show that the peptide combined with the PARP inhibitor olaparib inhibited the formation of clonal spheres in triple-negative breast cancer cells; A shows that the peptide combined with olaparib inhibited the formation of clonal spheres in MDA-MB-231 cells; B shows that the peptide combined with olaparib inhibited the formation of clonal spheres in HCC1937 cells. Figure 7 The results show the effects of peptide combined with the PARP inhibitor olaparib in inducing apoptosis in triple-negative breast cancer cells; A shows the apoptosis of MDA-MB-231 cells induced by peptide combined with olaparib; B shows the apoptosis of HCC1937 cells induced by peptide combined with olaparib. Figure 8 The results show the inhibition of human breast cancer xenograft tumors in nude mice by the combination of the peptide and the PARP inhibitor olaparib. A represents the results of euthanasia of nude mice 15 days after administration of the DMSO control group, 25 mg / kg peptide, 50 mg / kg olaparib, and the combination of peptide and olaparib, with tumor tissue dissected and photographed. B represents the tumor weight after drug treatment. C represents the tumor volume measurement results, presented as a line graph. D represents the nude mouse body weight measurement results, presented as a line graph. EF represents the results of anesthetizing nude mice after drug administration, collecting orbital blood, and measuring serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities to assess the hepatotoxicity of the combination drugs, and measuring serum creatinine levels to evaluate the nephrotoxicity of the combination drugs. Detailed Implementation

[0019] The technical solutions of the present invention will be further described in detail below with reference to the accompanying drawings and specific embodiments, but the present invention is not limited to the following technical solutions.

[0020] In the following examples, the human triple-negative breast cancer cells were MDA-MB-231 and HCC1937. The conventional cancer cells used above were all derived from Kunming Medical University. Among them, the BRCA gene in the breast cancer cell MDA-MB-231 was wild-type, and the BRCA gene in the breast cancer cell HCC1937 was mutant.

[0021] Unless otherwise specified, all reagents used in the embodiments of this invention are commercially available. RPMI 1640 and DMEM media were purchased from Gibco, fetal bovine serum from Biological Industries, phosphate-buffered saline (PBS), 0.25% trypsin (containing EDTA), and CCK8 reagent from Beyotime Biotechnology Co., Ltd.

[0022] Cell lines were cultured in DMEM or RPMI 1640 medium containing 10% fetal bovine serum at 37°C, 5% CO2 and 90% humidity.

[0023] The polypeptide sequence used in the following examples is shown in SEQ ID NO:1 (YGRKKRRQRRRFWDEPSEEWFWW). In the following examples, the last amino acid Trp of the polypeptide sequence is protected by an amino group (the sequence and structure are the same as those in patent number 202510073910.0). The structural formula is shown below. The polypeptide synthesis was commissioned to Wuhan Baiyixin Biotechnology Co., Ltd.

[0024]

[0025] The PARP inhibitor olaparib has the structural formula shown in Formula I, the PARP inhibitor tapozoparib has the structural formula shown in Formula II, and the CDK4 / 6 inhibitor ribociclib has the structural formula shown in Formula III. Olaparib, tapozoparib, and ribociclib were all purchased from Shanghai Taoshu Biotechnology Co., Ltd.

[0026]

[0027] Example 1: Results of synergistic inhibition of triple-negative breast cancer cell proliferation by peptides and PARP inhibitors. The CCK-8 assay is a highly sensitive method for detecting the number of live cells in cell proliferation or toxicity experiments. CCK-8 contains a water-soluble tetrazolium salt, WST-8, which is reduced by dehydrogenases in cells to a highly water-soluble yellow formazan product under the action of the electron carrier 1-methoxy-5-methylphenazine dimethyl sulfate. This product produces an absorption peak at a wavelength of 450 nm, and the absorbance value is linearly positively correlated with the cell count. Therefore, it can be used for the quantitative detection of cell count.

[0028] First, the IC50 values ​​of the peptide, olaparib, and tapazoli were determined using a CCK-8 assay. 50 Value, then based on IC 50 The concentration gradient of the combined drugs was set. MDA-MB-231 and HCC1937 cells were seeded into six 96-well plates, with 1 × 10⁶ cells seeded per well. 4Cells were selected and treated after adhesion. The combination of peptide and olaparib was administered to 1-3 wells, and the combination of peptide and taprazoprazrib was administered to 4-6 wells. Peptide was administered along the X-axis of the 96-well plate in ascending order of concentration, while olaparib or taprazoprazrib was administered along the Y-axis in ascending order of concentration. After 72 h, 10 μL of CCK8 solution was added to each well, and the cells were incubated in the dark for 1 h. The absorbance at 450 nm was measured using a microplate reader, and the inhibition rate of cell proliferation for each drug combination was calculated. The dose-response matrix heatmap of the drug combinations was analyzed using the SynergyFinder (https: / / synergyfinder.fimm.fi / ) server, and the Highest Single Agent (HSA) synergistic effect score was calculated. A synergistic effect score >10 indicated a synergistic effect between the two drugs, a score < -10 indicated an antagonistic effect, and a score between -10 and 10 indicated an additive effect.

[0029] Figure 1 The results showed that the synergistic effect scores of the peptide and olaparib in BRCA wild-type breast cancer cells MDA-MB-231 and BRCA-mutated breast cancer cells HCC1937 were 26.038 and 24.013, respectively. Figure 2 The results showed that the synergistic effect scores of the peptide and tprazole were 22.801 and 13.591, respectively. This indicates that the combination of the peptide and the PARP inhibitor has a good synergistic inhibitory effect on both wild-type and mutant BRCA breast cancer cells.

[0030] Notably, the composition provided by this invention exhibits a particularly outstanding synergistic effect score in BRCA wild-type breast cancer cells (MDA-MB-231). This suggests that this combination strategy holds promise for providing a new treatment option for BRCA wild-type patients, who currently lack effective PARP inhibitor treatments and account for a higher proportion of TNBC, thereby potentially expanding the clinical application scope of PARP inhibitors.

[0031] Example 2: Results of synergistic inhibition of triple-negative breast cancer cell proliferation by peptides and CDK4 / 6 inhibitors. The drug combination in Example 1 was replaced with a peptide and the CDK4 / 6 inhibitor ribociclib, with other procedures remaining the same as in Example 1. The synergistic inhibitory effect of the peptide and the CDK4 / 6 inhibitor ribociclib on breast cancer was detected. The results are as follows: Figure 3As shown, in MDA-MB-231 cells, the synergistic effect score of the combined treatment with the peptide and ribociclib was 9.106, indicating no significant synergistic effect; in HCC1937 cells, the synergistic effect score of the combined treatment with the peptide and ribociclib was only 4.184, also showing no synergistic effect. These results indicate that the combined use of the peptide and ribociclib, an inhibitor of CDK4 / 6, another target of breast cancer treatment, did not produce a significant synergistic inhibitory effect on breast cancer cells.

[0032] Example 3: Synergistic downregulation of FANCD2 protein expression by peptide and olaparib The peptide can target and inhibit the SND1-MTDH complex (the peptide is derived from patent ZL202510073910.0), and the DNA damage repair gene FANCD2 is a downstream gene regulated by SND1-MTDH. Human breast cancer MDA-MB-231 and HCC1937 cell lines were treated with different concentrations of the peptide for 48 hours, and the FANCD2 protein content was detected by Western blotting.

[0033] like Figure 4 As shown in Figure A, with the increase of peptide concentration (0 μM, 0.25 μM, 0.5 μM and 1.0 μM), the expression level of FANCD2 protein in MDA-MB-231 and HCC1937 cells decreased significantly in a dose-dependent manner, which directly proves that the peptide of the present invention can effectively inhibit the function of key proteins in DNA interstrand crosslinking repair.

[0034] like Figure 4 As shown in Figure B, compared with the single-drug treatment, the expression of FANCD2 protein was downregulated more significantly in the two-drug combination treatment group. This indicates that the peptide and olaparib have a synergistic effect in inhibiting FANCD2 expression, laying the molecular basis for subsequent DNA damage accumulation and cell death.

[0035] Example 4: The peptide and olaparib synergistically induce DNA damage and inhibit breast cancer cell proliferation. FANCD2 is a key gene regulating the repair of DNA interstrand crosslinking damage. Knockout of FANCD2 increases DNA damage in tumor cells, inhibits cell proliferation, and induces apoptosis. After DNA damage occurs, histone H2AX is rapidly phosphorylated to form γ-H2AX; therefore, γ-H2AX can serve as a biomarker for assessing the severity of cellular DNA damage. Human breast cancer MDA-MB-231 and HCC1937 cells were treated alone or in combination with 1 μM peptide and 2.5 μM olaparib. The inhibitory effect on cell proliferation was detected by CCK8 assay, and the γ-H2AX content was detected by Western blotting to assess the degree of cellular DNA damage. In the in vitro synergistic regimen shown in this example, 1 μM peptide (molecular weight approximately 3.09 kDa) and 2.5 μM olaparib (molecular weight approximately 434.5 Da) were used in combination, with a calculated mass ratio of approximately 2.9:1.

[0036] like Figure 5 A and Figure 5 As shown in Figure B, in MDA-MB-231 and HCC1937 cells, the combination treatment with the peptide and olaparib showed a stronger cell proliferation inhibition rate and a higher level of expression of the DNA damage marker γ-H2AX protein compared to the solvent control group and either single-drug treatment group. These results indicate that the composition of the present invention can synergistically induce severe DNA damage in breast cancer cells, thereby leading to cell growth arrest, and its effect is significantly superior to single-drug treatment.

[0037] Example 5: Synergistic inhibition of breast cancer cell clonal spheroid formation by peptides and olaparib Clonal sphere formation assays can assess the stemness and proliferative capacity of tumor cells and screen for sensitive drugs. Human breast cancer cells MDA-MB-231 and HCC1937 were seeded into 6-well plates. After adhesion, they were treated with 1 μM peptide and 2.5 μM olaparib alone or in combination. After 15 days of culture, the cells were fixed with 4% paraformaldehyde, stained with crystal violet, and photographed to count the number of clonal spheres. Figure 6 As shown, both BRCA wild-type breast cancer cells MDA-MB-231 and BRCA-mutated breast cancer cells HCC1937 exhibit strong clonal spheroid formation capabilities, indicating that both cell lines possess strong stemness and proliferative capacity. The peptide alone, when used with olaparib, inhibits the formation of clonal spheroids in both MDA-MB-231 and HCC1937 cells, while the combination of the peptide and olaparib further synergistically inhibits the formation of clonal spheroids in both MDA-MB-231 and HCC1937 cells. The composition of this invention effectively inhibits the clonal formation ability of breast cancer cells, suggesting that this combined strategy has the potential to more effectively target tumor cell populations with stemness characteristics, thereby offering a potential advantage in preventing tumor recurrence.

[0038] Example 6: Synergistic induction of apoptosis in breast cancer cells by peptides and olaparib Severe intracellular DNA damage activates the apoptosis program. Human breast cancer cells MDA-MB-231 and HCC1937 were treated with 1 μM peptide and 2.5 μM olaparib alone or in combination for 48 hours. Apoptosis was quantitatively detected using a dual fluorescent labeling method with Annexin V and propidium iodide (PI) combined with flow cytometry. Figure 7 As shown, the peptide and olaparib alone can induce apoptosis in MDA-MB-231 and HCC1937 cells, while the combination of the peptide and olaparib can further synergistically induce apoptosis in MDA-MB-231 and HCC1937 cells. The pharmaceutical composition of this invention can significantly activate the apoptosis program of breast cancer cells, suggesting that this combined strategy has the potential to more effectively eliminate tumor cells, thus offering a potential advantage in inhibiting tumor progression.

[0039] Example 7: Synergistic Inhibition of Breast Cancer Growth by Peptide and Olaparib in Vivo MDA-MB-231 cells were cultured, and cells were collected by trypsin digestion and centrifugation. After washing with PBS, the cells were resuspended and counted, and the cell concentration was adjusted to 2 × 10⁻⁶. 7 Cells / ml, 50 μL of cell suspension (i.e., 1×10⁶ cells / ml) was collected at each point. 6 Add 50 μL of matrix gel to each cell and mix well. Inject the mixture into the axilla of nude mice using a syringe. Wait until the subcutaneous tumor reaches a volume of 50-70 mm². 3 Nude mice were randomly divided into four groups: a DMSO control group, a peptide (25 mg / kg) group, an olaparib (50 mg / kg) group, and a peptide + olaparib group, with five mice in each group. Both the peptide and the compound were prepared using 10% DMSO, 5% Tween 80, 40% PEG 400, and 45% phosphate buffer. Each mouse received 100 μL of the drug via intraperitoneal injection. The DMSO control group received the drug-free solution. Administration was once daily for 14 consecutive days. Mouse weight was measured periodically, and tumor volume was measured (tumor volume = 0.5 × long axis × wide axis). 2 After administration, nude mice were euthanized by cervical dislocation, tumor tissue was removed, weighed, photographed, and serum was collected to assess drug hepatotoxicity and nephrotoxicity.

[0040] In the in vivo synergistic treatment regimen shown in this embodiment, the dosage of the peptide is 25 mg / kg, the dosage of olaparib is 50 mg / kg, and the mass ratio of the two combined is 1:2.

[0041] Figure 8 The results show the inhibitory effects of the peptide and olaparib on human breast cancer in vivo. Figure 8 A is a photograph of the tumor. Figure 8 B represents the tumor weight. Figure 8C represents the tumor volume change curve. Compared with the DMSO control group, both 25 mg / kg peptide and 50 mg / kg olaparib alone significantly inhibited tumor growth. Compared with single-drug administration, the combination of peptide and olaparib significantly inhibited tumor growth, indicating that peptide and olaparib have a synergistic inhibitory effect on breast cancer growth in vivo. The effects of peptide, olaparib, or combination therapy on body weight, serum alanine aminotransferase (ALT) levels, serum aspartate aminotransferase (AST) levels, and serum creatinine levels in nude mice were investigated. Figure 8 (DG) had no effect. The combination of the peptide and olaparib showed good synergistic anti-breast cancer activity in vivo, effectively inhibiting the in vivo growth of BRCA wild-type breast cancer cells, and had no hepatotoxicity or nephrotoxicity.

[0042] In summary, tumor cells, due to their high replication pressure, defects in their DNA repair systems (such as BRCA mutations), or dependence on oncogenes (such as high expression of the SND1-MTDH complex), have significantly lower genomic stability than normal cells and are more sensitive to DNA damage repair inhibition. The combination strategy of this invention is based on this principle. First, the peptide targets the SND1-MTDH complex, which is specifically highly expressed or abnormally active in breast cancer, and has relatively little impact on normal cells. Second, the 'synthetic lethal' effect of PARP inhibitors on DNA repair defects (such as BRCA mutations) inherently possesses a certain degree of tumor selectivity. Finally, as (… Figure 8 As shown in the DG, at doses that effectively inhibit tumors, the combination therapy did not cause significant weight loss or abnormal liver and kidney toxicity indicators in nude mice. This preliminarily demonstrates in vivo that the combination therapy has a good safety window and tumor selectivity.

[0043] It should be noted that the embodiments described above are only for explaining the present invention and do not constitute any limitation on the present invention. The present invention has been described with reference to typical embodiments, but it should be understood that the words used therein are descriptive and explanatory terms, not limiting terms. Modifications can be made to the present invention within the scope of the claims, and revisions can be made to the present invention without departing from the scope and spirit of the present invention. Although the present invention described herein relates to specific methods, materials, and embodiments, it does not mean that the present invention is limited to the specific examples disclosed herein; on the contrary, the present invention extends to all other methods and applications having the same function.

Claims

1. The use of a composition of a polypeptide and a PARP inhibitor in the preparation of a drug for treating breast cancer, characterized in that: The polypeptide is a polypeptide that targets the SND1-MTDH complex, and its amino acid sequence is shown in SEQ ID NO: 1; the PARP inhibitor is one or both of olaparib and tapazoli.

2. The use of the composition of the polypeptide and PARP inhibitor according to claim 1 in the preparation of a drug for treating breast cancer, characterized in that: The last amino acid Trp in the polypeptide sequence is protected by an amino group.

3. The use of the composition of the polypeptide and PARP inhibitor according to claim 1 in the preparation of a drug for treating breast cancer, characterized in that: The PARP inhibitor is olaparib or a pharmaceutically acceptable salt thereof.

4. The use of the composition of the polypeptide and PARP inhibitor according to claim 1 in the preparation of a drug for treating breast cancer, characterized in that: The PARP inhibitor is tapolaparib or a pharmaceutically acceptable salt thereof.

5. The use of the composition of the polypeptide and PARP inhibitor according to claim 1 in the preparation of a drug for treating breast cancer, characterized in that: The mass ratio of the polypeptide to the PARP inhibitor is 1:10 to 10:

1.

6. The use of the composition of the polypeptide and PARP inhibitor according to claim 1 in the preparation of a drug for treating breast cancer, characterized in that: The breast cancer mentioned is basal-like triple-negative breast cancer, including BRCA wild-type breast cancer subtypes or BRCA-mutated breast cancer subtypes.

7. The use of the composition of the polypeptide and PARP inhibitor according to claim 1 in the preparation of a drug for treating breast cancer, characterized in that: The breast cancer in question is BRCA wild-type triple-negative breast cancer.

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