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Ovarian cancer is one of the most common malignant tumors in the female reproductive system, and the onset is hidden. Many patients are already in the late stage of the disease when they are in the treatment. The main treatment method is surgery and combined chemotherapy mainly composed of platinum and paclitaxel. Although the initial efficacy of
is still acceptable, with the deepening of treatment, the resistance of chemotherapy has gradually emerged. 70% of patients relapse within 2 to 3 years, and the survival rate has been significantly reduced. Fortunately, in recent years, the polyadenylase diphosphate polymerase (PARP) inhibitor has appeared in ovarian cancer, bringing new treatment hopes to patients [1].
Image source: Photo Network
However, while I was happy, many patients were also full of doubts about it. Recently, a patient expressed his concern to us in the background: "I heard that if you receive chemotherapy after using PARP inhibitors, the sensitivity of treatment will decrease, and you may even become resistant to chemotherapy. Is this true?" To answer this question, we must first understand what PARP inhibitors are.
01, What is a PARP inhibitor? How to treat ovarian cancer?
We all know that if all cells in our body (including cancer cells) have their own DNA damage and cannot be effectively repaired, they will eventually go to apoptosis. PARP inhibitors are actually a drug that has the ability to inhibit the DNA repair of cancer cells. So how does it treat ovarian cancer? We also have to start with the BRCA1/2 gene.
Breast cancer susceptibility gene (BRCA1/2) is an important tumor suppressor gene and plays an important role in DNA damage repair and normal cell growth. The BRCA1/2 mutation will inhibit the ability of cell DNA to repair normally after it is damaged, and eventually lead to cell carcinogenesis. Fortunately, in addition to BRCA1/2, PARP also occupies a place in the process of promoting cell DNA repair. Although the repair path is different from the former, it can make up for the loopholes of BRCA1/2 dereliction of duty and ensure the normal development of cells. However, this also invisibly gives cancer cells an opportunity to survive intact when a DNA repair path is damaged [1-2].
Repair process for damage to DNA of normal cells and BRCA mutant cells[3]
Therefore, if you want to cut off all retreats of cancer cells, you must also destroy the function of PARP repairing DNA in cancer cells. PARP inhibitors are a good choice. They can devastatingly strike the ability of cancer cells to repair DNA damage, so that they cannot be repaired effectively, thereby promoting the apoptosis of cancer cells. This mechanism of killing cancer cells is called "synthetic lethal" [3].
After adding PARP inhibitor, the repair process of DNA damage of normal cells and BRCA mutant cells is damaged [3]
It should be noted that since normal cells do not have BRCA1/2 mutations, even if the PARP inhibitor destroys the function of PARP repair DNA, there is still a repair path of BRCA1/2 that can be followed, so it will not go to apoptosis [3].
02. Will it be resistant to drug after using PARP inhibitors?
There is currently no study supporting the statement that "it will be resistant to chemotherapy after using PARP inhibitors."
study shows that the PARP gene is abnormally sensitive to DNA damage caused by factors such as radiation and chemotherapy drugs, and can quickly mobilize the body's functions to repair it, which greatly weakens the sensitivity of chemotherapy. "silence" the PARP gene or the rational use of PARP inhibitors can effectively improve the chemotherapy sensitivity of ovarian cancer drug-resistant cells to cisplatin drugs, avoid the occurrence of chemotherapy resistance, and improve the anti-tumor activity of chemotherapy drugs. Therefore, after using PARP inhibitors, there will be no resistance to drug after receiving chemotherapy [4].
Secondly, the "Guidelines for Clinical Application of PARP Inhibitors for Ovarian Cancer (2022 Edition)" mentioned that the drug toxicity of PARP inhibitors is generally lower than that of chemotherapy drugs. It is currently mainly used for maintenance treatment after remission of ovarian cancer treatment and post-line treatment for patients with recurrent ovarian cancer. It can also be used as a "chemotherapy" therapeutic drug for ovarian cancer patients with positive BRCA1/2 mutations and/or homologous recombination defects [1].
Image source: Photo Network
In addition, the currently marketed PARP inhibitors (such as olaparib, niraparib, etc.) have shown good efficacy in patients with ovarian cancer resistant to platinum chemotherapy drugs and refractory BRCA1/2 mutations or homologous recombination defects. At the same time, a number of clinical trials of combined PARP inhibitors with other chemotherapy drugs for the treatment of ovarian cancer are also underway. We look forward to the release of new clinical data in the future to surprise us [5].
END
In short, in the treatment of ovarian cancer, the use of chemotherapy drugs has indeed effectively prolonged the patient's survival and improved the prognostic effect of treatment. However, the emergence of chemotherapy resistance has once again seized the opportunity, bringing severe consequences to the patients' subsequent treatment.
Fortunately, PARP inhibitors come from behind and have their own "synthetic lethal" anti-tumor halo, which has changed the treatment model of ovarian cancer in one fell swoop, significantly prolonged the patient's survival, and brought new treatment hopes to patients. We hope that it will once again gain inspiring clinical data in future combination treatment.
Editor in charge: Gynecological tumor mutual aid Jun
Picture source: Photo Network
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