Domestic Researchers Uncover Mechanism of Resistance to Olaparib, a Game Changer for Ovarian Cancer

Domestic researchers have identified the characteristics of patients showing resistance to 'Olaparib' (brand name Lynparza), known as a 'game changer' in ovarian cancer treatment, drawing attention from the academic community. This is expected to provide new clues for treating recurrent ovarian cancer patients.

Korea AstraZeneca Linfaza Tablets. [Photo by Korea AstraZeneca]

The research team, led by Professor Lee Jung-yoon and Lecturer Kim Yuna from the Gynecologic Cancer Center at Yonsei Cancer Hospital, along with Professor Lee Seung-tae and researcher Shim Ye-eun from the Department of Laboratory Medicine at Yonsei University College of Medicine, analyzed circulating tumor DNA extracted from the blood of ovarian cancer patients with BRCA gene mutations and successfully identified the mechanism of resistance to 'PARP inhibitors.'

BRCA gene mutations are one of the causes of ovarian cancer. The BRCA gene normally functions as a tumor suppressor, but when mutated, it induces ovarian cancer. Olaparib, a targeted therapy drug, inhibits the PARP protein that targets these mutations. According to treatment outcome analysis studies, Olaparib has revolutionized ovarian cancer treatment by increasing the 5-year survival rate from 38.1% to 73.1%.

However, Olaparib also has drawbacks. Resistance develops after a certain period of use. About half of the patients who used Olaparib as initial treatment develop resistance within five years. It is known that problems in homologous recombination, which repairs damaged DNA based on normal DNA information, replication forks that initiate new double-stranded DNA structures, signaling pathways sent by cancer cells for survival, and proteins targeted by PARP inhibitors cause resistance.

Professor Lee Jung-yoon and Lecturer Kim Yuna from Yonsei Cancer Hospital Gynecologic Cancer Center, Professor Lee Seung-tae and Researcher Shim Ye-eun from the Department of Laboratory Medicine, Yonsei University College of Medicine (from left).

To identify the characteristics of patients with Olaparib resistance, the research team analyzed 'Circulating Tumor DNA (ctDNA)' obtained from blood. Circulating tumor DNA is material shed from cancer cells into the bloodstream, which can reveal cancer characteristics and is gaining attention for its use in early diagnosis, treatment efficacy monitoring, and discovery of drug resistance mechanisms. The team first compared ctDNA before treatment and after recurrence in 29 ovarian cancer patients who relapsed after using Olaparib. Patients whose blood tests before treatment already showed known resistance mechanisms did not respond to PARP inhibitors. It was also found that recurrent patients simultaneously possessed various resistance mechanisms.

Next, the team investigated why PARP inhibitors initially worked but suddenly became ineffective. The results showed that at the time of recurrence, the number and types of mutated cancer cells increased, and 89.7% of recurrent patients exhibited new mutations that were not detectable before treatment. Among these, mutations in genes involved in the cell cycle such as ATM, CHEK3, and TP53 accounted for more than half. When comparing patients with mutations related to homologous recombination and those without, those with mutations had the worst treatment outcomes and survival rates after recurrence. Furthermore, treatment efficacy decreased more when multiple resistance mechanisms were present compared to having just one.

Professor Lee Jung-yoon explained, "Obtaining ovarian cancer tumors before and after treatment is often difficult depending on tumor location, limiting confirmation of Olaparib resistance. Since gene mutations causing Olaparib resistance were identified using circulating tumor DNA, which can be relatively easily obtained from blood, new therapeutic clues for recurrent patients have been established." The study results were published in the international journal Clinical Cancer Research (IF 13.801).