Study uncovers key driver of aggressive ovarian cancer

Despite representing only 3% of all female tumors, ovarian cancer is the fifth leading cause of cancer death in women. It is estimated that by 2024, nearly 3,800 women will be diagnosed with this disease in Spain. Now, a new study explains the genetic basis of a rare and aggressive form of ovarian cancer and offers a potential avenue for new treatments.

This is high-grade serous carcinoma, the most common type of ovarian cancer, which is usually detected at an advanced stage and becomes resistant to current chemotherapy treatments. Its underlying genetics are complex, with multiple alterations and genetic instabilities. One of the genes implicated is CDK12, an oncogenic trigger also linked to other cancers, including breast cancer, prostate cancer, and stomach cancer.

In this new study, published in PNAS , researchers at the University of Michigan (USA) have used a novel mouse model showing that CDK12 acts as a tumor suppressor to drive high-grade serous carcinoma arising in the murine oviduct, the equivalent of the human fallopian tube. A promising degrader targeting CDK12 and a related gene, CDK13, can destroy these tumors.

"This is the first demonstration in a mouse model that CDK12 plays a tumor suppressor role in this type of cancer. When CDK12 is inactivated, tumors grow much faster and mice die sooner, demonstrating that this is a more aggressive form of the disease," said Arul M. Chinnaiyan , co-senior author of the study.

The mouse model used in this work was crucial to the discovery. It was based on a genetic engineering model previously created by Kathleen R. Cho , in which three genes known to suppress the development of high-grade serous carcinoma were deleted from the mouse oviduct. In this case, CDK12 was added to achieve a quadruple gene inactivation.

The result allowed the researchers to observe that, in addition to promoting aggressive tumor growth, the inactivation of CDK12 triggered a cellular immune response .

Furthermore, the researchers identified an associated gene, CDK13, as a target for a CDK12 degrader or inhibitor. In their work, this strategy reduced tumor growth, suggesting that a combination therapy could be effective in this subgroup of ovarian cancers.

Although some improvements have been made in the treatment of high-grade serous carcinoma, once patients develop resistance to first-line chemotherapy , the selection of other chemotherapy agents is largely a matter of guesswork. New treatments are urgently needed, as overall survival for women with this type of cancer remains quite low.

This team previously reported similar findings in prostate cancer, showing that CDK12 is a key factor in disease aggressiveness.