Peking University identifies MACIR protein as ‘key to resistance’ in ovarian cancer, opening potential new treatment strategy

A team led by Professors Wang Weibin and Wang Zhidong of Peking University in China has identified the role of MACIR (C5orf30), a protein that regulates DNA damage repair, for the first time worldwide in the international journal PNAS. The study confirmed that this protein acts as a key regulator that helps cancer cells repair DNA and that inhibiting it makes ovarian cancer cells much more responsive to platinum-based anticancer drugs. The findings are drawing attention because they provide the first molecular biological clue toward overcoming platinum resistance, the greatest challenge in ovarian cancer treatment.

Ovarian cancer is a deadly disease that ranks among the leading causes of cancer death in women worldwide. Because it causes few early symptoms, 70%–80% of all patients are diagnosed only after the disease has progressed to stage 3 or later.

Even after surgery and first-line platinum-based chemotherapy, approximately 70%–80% of patients experience recurrence within 3–5 years, and approximately 16.9%–20% of these patients develop platinum-resistant ovarian cancer (PROC), defined as recurrence within 6 months after completion of treatment. The median progression-free survival of patients who develop platinum resistance is approximately 4.75 months, and overall survival is only 9–12 months.

■ Relationship between the RAD51 complex and MACIR

Platinum-based anticancer drugs, such as cisplatin and carboplatin, which are the first-line standard treatment for ovarian cancer, induce cell death by causing cross-linking damage to cancer cell DNA. However, cancer cells survive by activating their own DNA repair system, known as homologous recombination (HR), in which the RAD51 protein complex plays a central role.

MACIR, identified by the Peking University researchers, is a regulatory protein that promotes disassembly of the RAD51 complex. In other words, when MACIR is activated, cancer cells repair DNA damage more efficiently and withstand the attack of anticancer drugs.

The researchers experimentally confirmed that blocking MACIR activity with small-molecule inhibitors (compounds 8 and 10) prevented cancer cells from repairing DNA damage and substantially increased their sensitivity to platinum-based anticancer drugs. They also presented a correlation showing that higher expression levels of the MACIR-FIRRM-FIGNL1 complex were associated with poorer outcomes in patients with ovarian cancer.

■ A problem directly relevant to patients with ovarian cancer in South Korea

The incidence of ovarian cancer in South Korea is also steadily increasing. According to the 2023 National Cancer Registry statistics, 3,299 patients with ovarian cancer were reported in the country, a 31% increase over 10 years.

Despite South Korea’s relatively high rate of early diagnosis, the 5-year relative survival rate for ovarian cancer is only 66.8%, the lowest among the major female cancers compared with breast cancer (94.8%) and uterine cancer (89.1%). Seven out of 10 patients in South Korea also experience recurrence and platinum resistance, creating substantial clinical demand for new treatment mechanisms.

The European Society for Medical Oncology (ESMO) has stated that “recurrent advanced ovarian cancer is an area that is virtually impossible to cure” and that “developing targeted therapies with new mechanisms that are effective for patients with platinum resistance is an urgent task for the oncology community worldwide.”

■ Potential for drug development and biomarker use

Industry experts are watching how quickly these findings can advance to the clinical stage, given that the study demonstrated efficacy at the laboratory level. If clinical trials combining MACIR-inhibiting small-molecule compounds with existing platinum-based anticancer drugs move forward in earnest, they could provide a practical alternative for patients with resistance.

The findings also raise the possibility of using MACIR complex expression levels measured in tumor tissue samples as a “predictive biomarker” to identify patients at high risk for platinum resistance in advance. This could help reduce unnecessary anticancer treatment and support the implementation of patient-specific precision medicine.

With PARP inhibitors targeting DNA repair mechanisms already established in ovarian cancer treatment, the MACIR inhibition mechanism could emerge as a next-generation licensing and investment target for global pharmaceutical companies. Because the platinum-resistant ovarian cancer market is an area in which unmet medical needs are rapidly growing, competition to develop related new drugs is also expected to accelerate.