KR101872624B1 - Method of predicting responsiveness of lung cancer treatment to alk targeting agent - Google Patents
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Abstract
Description
The present invention relates to a method for predicting the reactivity of a non-small cell lung cancer patient against a drug targeting an anaplastic lymphoma kinase (ALK).
Cancer can be categorized into surgery, radiation therapy, chemotherapy, and biological therapy. Of these, patients who do not readily undergo surgery or radiation therapy (about 50% of all cancer patients) and patients who have already metastasized are treated with chemotherapy. In the case of drugs used for chemotherapy, various types of cancer Efforts have been made to isolate components having anticancer effects through evaluation of efficacy using cell lines and animal tumor models. However, the conventional anticancer agent still has a problem of attacking not only cancer cells but also rapidly dividing normal cells, thereby causing serious side effects.
Since the target anticancer agent attacks only a specific target expressed only in cancer cells, it has an advantage of maximizing the therapeutic effect while minimizing adverse effects as seen in the conventional anticancer drugs. However, in the case of a target therapeutic, it is effective only when a specific therapeutic target is expressed, not effective against all cancers. Therefore, before using the target therapeutic, it is necessary to confirm the gene change in the patient's tumor and use a target therapeutic agent And even if it is a target treatment agent, there is very little side effect rather than the existing anticancer agent, but there is no side effect at all, and there is a problem that the treatment effect is not shown or the therapeutic response is not shown after a certain time.
Thus, one of the obstacles to cancer treatment using chemotherapy is anticancer drug resistance. Drug resistance to anticancer drugs refers to the case where cancer cells do not die despite the administration of an anticancer drug in an amount that can reach the blood concentration that can kill the cancer cells. Anticancer drug resistance may vary from patient to patient and may even be caused by a variety of factors including genetic differences between tumors derived from the same tissue.
The anticancer drug resistance mechanism is generally classified into extracellular resistance and intracellular resistance. The extracellular resistance may be caused by the fact that the cancer cells of the patient are in vitro not only in the case where a sufficient dose of the anticancer drug is administered and the intestinal absorption is abnormally lowered as in the case of the oral anticancer drug, Since they are not exposed to concentrations that can kill cancer cells, they may show resistance to anticancer drugs. Or in a pharmacologic sanctuary where the drug has reached a sufficient blood level but has poor blood flow to cancerous tissues or physiologically has a blood-tissue barrier between blood vessels and cancerous tissues Even when cancer cells are not exposed to a sufficient concentration of anticancer drugs as in the case of cancer cells, they show anticancer drug resistance. In this regard, Korean Patent Laid-Open Publication No. 2013-0058631 discloses a method for overcoming tolerance of a target anticancer drug.
It is very important to determine the therapeutic response and effectiveness of a specific anticancer drug by determining whether or not the cancer patient has acquired cancer resistance. As a representative example, lapatinib, a breast cancer treatment, has been found to have a therapeutic effect when the level of HER2 protein is high (HER2-positive) and the level of EGRF protein is low. However, metastatic HER2 negative breast cancer did not respond to lapatinib, indicating that lapatinib was ineffective. These results suggest that patients with breast cancer need to know precisely whether they are HER2 negative or positive before treatment, so that appropriate treatment can be selected.
Lung cancer is the leading cause of cancer deaths worldwide and can be divided into non-small cell lung cancer and small cell lung cancer, depending on the type of lung cancer cells. Approximately 80% of lung cancers are classified as non-small cell lung cancer, including adenocarcinoma, squamous cell carcinoma, and large cell carcinoma. In addition, non-small cell lung cancer generally has a slower transition to other organs than small cell lung cancer.
On the other hand, degenerative lymphoma kinase (ALK), also known as ALK tyrosine kinase receptor or CD246 (cluster of differentiation 246), is an enzyme encoded by the ALK gene. ALK plays an important role in brain development and affects specific neurons in the nervous system It is known to have an effect.
A variety of ALK target drugs have been developed to treat epithelial cancers such as lung cancer, breast cancer, bladder cancer and stomach cancer, and in particular, drugs such as Crizotinib (Pfizer, trade name "Xalkori") and Ceritinib , Inhibits the tyrosine kinase activity of ALK and prevents cancer cell growth.
Although these target therapeutics are highly effective drugs, there is a problem in that they do not exhibit resistance to measurable effects or resistance to therapeutic effects in continuous use. In fact, only about 10% of patients with non-small cell lung cancer are responding to these drugs.
Accordingly, the present inventors have made intensive efforts to provide a method of predicting the therapeutic response and the effect of a specific anticancer agent by judging whether the cancer patient is resistant to the anticancer drug.
That is, an object of the present invention is to provide ANT2 as a novel resistance-prediction biomarker for treatment of crytotinib in lung cancer patients, and more particularly, The present invention provides a method for identifying or predicting patients with non-small cell lung cancer who are resistant to anaplastic lymphoma kinase (ALK) target drug.
However, the technical problem to be solved by the present invention is not limited to the above-mentioned problems, and other matters not mentioned can be clearly understood by those skilled in the art from the following description.
The present invention provides a method for predicting the reactivity of non-small cell lung cancer patients against a drug targeting degenerative lymphoma kinase (ALK), comprising the step of confirming the expression level of ANT2 protein or mRNA in a lung cancer tissue sample .
In one embodiment of the present invention, the drug of the method is characterized by being Crizotinib, Ceritinib or Entrectinib.
In another embodiment of the present invention, the expression level of the ANT2 protein is characterized by immunohistochemical staining and expression of ANT2 mRNA using qRT-PCR.
In another embodiment of the present invention, the immunohistochemical staining is characterized by using an anti-ANT2 antibody.
According to the present invention, it is possible to predict in advance whether or not a lung cancer patient will respond to a drug treatment agent, thereby solving the problem of low treatment success rate due to immunity.
Further, according to the present invention, it is possible to determine whether a patient is responsive to a drug used for treating lung cancer, estimate the prognosis of the anticancer drug, and determine the future treatment policy.
FIG. 1 shows the results of confirming the expression level of ANT2 mRNA and protein in lung cancer cell line H3122 showing high therapeutic reactivity (cytotoxic effect) to crytotinib and H3122CR (crizotinib resistant) lung cancer cell line showing resistance FIG.
FIG. 2 shows the results of ANT2 immunohistochemical staining (ANT2 protein) in lung cancer tissues of lung cancer patients, comparing the ANT2 expression level before and after acquiring the anticancer drug response, the ANT2 expression level, and the anticancer drug resistance FIG.
The present invention shows that the expression of ANT2, which is highly expressed in cancer cells that have acquired anticancer drug resistance, is highly expressed in most cancer cells, and it is judged whether or not the anticancer drug resistance is obtained and the therapeutic response and effect (ANT2 protein) and qRT-PCR (ANT2 mRNA) were performed in lung cancer tissues of lung cancer patients, and the anticancer drug response, ANT2 expression level, and anticancer drug And the degree of ANT2 expression before and after obtaining the resistance was compared.
At this time, the cancer patients designated as the study subjects are lung cancer patients treated with Crizotinib, a treatment for lung cancer. Lung cancer is a very deadly cancer with the highest cancer mortality worldwide. Non-small cell lung cancer, which accounts for the majority of lung cancer, is almost impossible to diagnose early, and early mortality is high due to good remote metastasis. About 40% -50% of patients with recurrent lung cancer are found at the first stage of lung cancer and have been treated surgically. The main therapeutic agents use conventional anticancer drugs, and recently targeted therapeutic agents such as Crizotinib, Ceritinib, and Anaplastic lymphoma kinase (ALK) have been widely used. It is of the ultimate interest in the art to find a predictive biomarker because these targeted therapies can only have a good effect when certain biomarkers are expressed in tumors.
In particular, CRIZOTINIB is an FDA-approved ALK inhibitor in 2011 and has few side effects and is used as a target treatment for patients with EML 4 (Echinoderm Microtubule-associated Protein-4) -ALK-positive non-small cell lung cancer.
The present invention uses ANT2 as a novel resistance prediction biomarker. The adenine nucleotide translocator (ANT) is an enzyme present in the inner membrane of the mitochondrial membrane (IM) through the VDAC (voltage dependent anion channel) of the outer membrane (OM) Is known to be an enzyme that imports and transporters ATP produced through an electron transfer chain system into the cytoplasm.
ANT1, ANT2 and ANT3, which are three isoforms, are known to play an essential role in energy metabolism of cells. Of these, ANT2 is expressed in normal cells but is highly expressed in cancer cells or cells with high proliferation ability Which is closely related to the glycolysis reaction in an anaerobic condition and has recently been shown as a target for a new cancer treatment.
That is, the present invention provides a method for predicting the responsiveness of a non-small cell lung cancer patient to a drug targeting an anlastoplastic lymphoma kinase (ALK), comprising the steps of:
Confirming the expression level of ANT2 (Adenine Nucleotide Translocator 2) protein or mRNA in a sample of lung cancer tissue, and
When the expression of ANT2 is higher than that of the control, it is judged that the reactivity of the non-small cell lung cancer patient is low for the drug that targets ALK.
In one embodiment of the present invention, the drug may be Crizotinib, Ceritinib or Entrectinib, and most preferably is selected from the group consisting of chrysotile- But is not limited thereto.
In another embodiment of the present invention, the expression level of the ANT2 protein may be determined using immunohistochemical staining. The immunohistochemical staining is performed using an anti-ANT2 antibody, and the expression level of ANT2 mRNA may be confirmed by using qRT-PCR as in the example of the present invention. However, the expression level of ANT2 protein can be quantitatively confirmed The method is not limited thereto.
In the examples of the present invention, it was confirmed that the drug reactivity of lung cancer patients can be predicted by confirming the increase of expression of ANT2 protein using immunohistochemical staining (Example 2). Herein, "immunohistochemistry" is a method of analyzing the expression pattern of a cell using an antigen-antibody reaction. When a tumor cell expresses a specific antigenic protein, when the antibody is reacted with a complementary antibody, the antibody specifically binds to a complementary antigen, and the antigen-antibody conjugated product is treated with a secondary antibody to amplify the reaction, , It can be objectively judged whether the tumor cells express the antigen (positive) or not (negative) by observation with a microscope.
Hereinafter, the present invention will be described in more detail with reference to examples. However, the following examples are only illustrative of the present invention, and the present invention is not limited to the following examples.
[Example]
Example 1. Analysis of ANT2 mRNA and protein expression levels in lung cancer cell lines
1-1. Lung cancer cell preparation
H3122 is an ALK mutant positive lung carcinoma cell line and H3122CR cell line is an artificial cell line produced by culturing H3122 cell line at a low concentration of chrysotanib (30 nM) for 6 months to induce resistance to clitorotinib. In the case of H3122, The H3122 cell line was purchased from the ATCC (American Type Culture Collection, US), and the H3122CR cell line was treated with H3122CR at a concentration of 50% Was provided by Professor Kim Tae Min of the Seoul National University.
1-2. Extraction of total RNAs and qRT-PCR in lung cancer cells
Total RNAs were extracted using Trizol in the lung cancer cell line prepared in Example 1-1, and qRT-PCR was performed using the PrimeScript first strand cDNA synthesis kit (Takara product) and SYBR. The apparatus was purchased from ABI product Step One Plus thermal cycler Respectively. The primer sequences used in qPCR are as follows.
ANT2: forward, 5'-ACGTGTCTGTGCAGGGTATT-3 '(SEQ ID NO: 1), and
reverse, 5 ' -GTGTCAAATGGATAGGAAG-3 ' (SEQ ID NO: 2);
GAPDH: forward 5'- CCCTTCATTGACCTCAACTA-3 '(SEQ ID NO: 3), and
reverse, 5'-ACGATACCAAAGTTGTCATG-3 '(SEQ ID NO: 4)
1-3. Protein extraction and western-blotting in lung cancer cells
For protein extraction, lysis buffer with the following composition was used:
L-phenylenediamine tetra-acetic acid, 300 nmol / L NaCl, 0.1% NP-40, 0.5 nmol / L NaF, 0.5 nmol / L Na3VO4, and 0.5 nmol / L phenylmethylsulfonyl fluoride, as well as 10 mg / mL each of aprotinin, pepstatin, and leupeptin; Sigma-Aldrich
Antibodies used for Western blot were ANT2 (Proteintech) and actin (Santa Cruz Biotechnology).
1-4. result
The results of confirming the protein expression level of ANT2 mRNA by Western blotting tgodgk as described above are shown in Fig. As shown in FIG. 1, the expression level of ANT2 mRNA and protein in lung cancer cell line H3122CR (crizotinib resistant) showing resistance to H3122, a lung cancer cell showing high therapeutic reactivity (cell killing effect) , Confirming that H3122CR has a higher expression of ANT2 than H3122, confirming that ANT2 can be used as a novel resistance prediction biomarker for the treatment of chrysotileum in lung cancer patients.
Example 2. Immunohistochemical staining of ANT2 protein in lung cancer tissue
Based on the results of Example 1, the present Example 2 was intended to determine whether resistance to lung cancer patients could be predicted. In the case of lung cancer patients, the therapeutic effect of gepetinib and the data on whether or not to acquire resistance were collected, , And immunohistochemical staining (IHC) of ANT2 protein was performed. The concrete method is as follows.
2-1. Preparation of lung cancer tissue
Lung cancer tissues were surgically removed from 10 lung cancer patients at Seoul National University Hospital and stored in liquid nitrogen until analysis.
2-2. Manufacture of tissue slides
The lung cancer tissue was made into a paraffin-embedded block, and cut with a microtome to a thickness of 4 袖 m and stuck on a glass slide to prepare a tissue slide. At this time, the slides were placed in a dry oven at 65 DEG C for 1 hour to prevent tissue from falling off. Then, xanthylene and alcohol were degassed for 40 minutes.
2-3. Pre-treatment of immunohistochemical staining
For the prepared tissue slides, microwave was irradiated three times for 5 minutes to expose ANT2 protein antigen. Then, 3% H 2 O 2 was treated for 15 minutes to remove blood, which is an intrinsic factor present in the tissue, and then blocked with normal serum for 1 hour to prevent nonspecific binding of the antibody.
2-4. Immunohistochemical staining
The primary antibody used for immunization was an anti-ANT2 antibody (Creative BioMart, Cat No. CAB4666MH, 1: 100 dilution), and the primary antibody was treated at room temperature for 1 hour without washing. After washing with water, the secondary antibody (biotinylated antibody) and streptavidin enzyme complex were treated for 20 minutes, washed with DAB, developed with DAB, and examined for color development. After washing with Mayer Hemtoxylin, the cells were washed again with water, dried and sealed with permount.
2-5. result
The results of comparing ANT2 expression by the above method are shown in Fig. As can be seen from FIG. 2, it was confirmed that ANT2 expression was relatively low in tissues of a patient group highly responsive to an anticancer agent, and that ANT2 expression was high in tissues of a patient group having low therapeutic response of an anticancer agent. In addition, ANT2 expression after treatment was significantly increased in patients who had good therapeutic response at the initial stage but had decreased therapeutic response after obtaining the anticancer drug resistance after treatment.
It will be understood by those skilled in the art that the foregoing description of the present invention is for illustrative purposes only and that those of ordinary skill in the art can readily understand that various changes and modifications may be made without departing from the spirit or essential characteristics of the present invention. will be. It is therefore to be understood that the embodiments described above are in all respects illustrative and not restrictive.
<110> BIOINFRA INC. <120> METHOD OF PREDICTING RESPONSIVENESS OF LUNG CANCER TREATMENT TO ALK TARGETING AGENT <130> MP16-536 <160> 4 <170> KoPatentin 3.0 <210> 1 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> ANT2_forward primer <400> 1 acgtgtctgt gcagggtatt 20 <210> 2 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> ANT2_reverse primer <400> 2 gtgtcaaatg gataggaag 19 <210> 3 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> GAPDH_forward primer <400> 3 cccttcattg acctcaacta 20 <210> 4 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> GAPDH_reverse primer <400> 4 acgataccaa agttgtcatg 20
Claims (5)
Confirming the expression level of ANT2 (Adenine Nucleotide Translocator 2) protein or mRNA in a sample of lung cancer tissue, and
When the expression of ANT2 is higher than that of the control, it is judged that the reactivity of the non-small cell lung cancer patient is low for the drug that targets ALK.
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US11506654B2 (en) | 2018-10-31 | 2022-11-22 | Korea Institute Of Science And Technology | Method, composition and kit for screening ALK or ROS-1 kinase inhibitor |
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Andrew J. Weickhardt et al., Cancer(2013), vol.119(8): 1467-1477. |
Ji-Young Jang et al., Molecular Cancer Therapeutics(2016.02.), vol.15(6): 1387-1396. * |
비소세포성폐암 세포에서 ALK 억제제의 내성기전연구, 서울대학교 석사학위논문(2016.08.), pp 1-62. * |
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US11506654B2 (en) | 2018-10-31 | 2022-11-22 | Korea Institute Of Science And Technology | Method, composition and kit for screening ALK or ROS-1 kinase inhibitor |
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