New way to improve breast cancer treatment outcomes

March 18, 2021

Breast cancer is the most common cancer in women worldwide and the second most common cancer overall. Although it can now be treated with drugs, many of these drugs mysteriously stop working after a while, causing a relapse.

Now a team of researchers from the Cancer Science Institute of Singapore (CSI Singapore) at the National University of Singapore (NUS), the Genome Institute of Singapore (GIS) under the aegis of the Agency for Science, Technology and research (A * STAR) and The National University Cancer Institute, Singapore (NCIS), as well as their international research collaborators in Denmark, have discovered why this is happening.

There are often multiple molecular pathways that stimulate cancer growth, and most targeted therapies only affect one molecular pathway. Drug resistance often develops due to the “rescue” of the other cancer pathway not targeted by drug therapy. The researchers found a solution – administer an additional drug that controls the second pathway.

The team, led by Professor Lee Soo Chin from CSI Singapore and NUS Yong Loo Lin School of Medicine and Professor Yu Qiang from GIS, focused on a protein called HER2 (Human Epidermal Growth Factor Receptor 2) , which, when present in excessive amounts, stimulates the cancerous growth of breast cells. Drugs that target HER2 are effective against breast cancer cells overexpressing HER2, but eventually these drugs become ineffective, and scientists don’t know why.

Deciphering the mechanisms of resistance of breast cancer to treatment targeting HER2

Scientists used existing data from a biochemical database and tumor samples from 29 patients enrolled in a clinical trial conducted at NCIS, to focus on an enzyme subunit called PPP2R2B (serine / threonine-protein phosphatase 2A 55 kDa regulatory subunit B beta isoform) which seemed to be in short supply in cancer cells whenever drugs targeting HER2 did not work.

The research team found that PPP2R2B suppresses cancer by making chemical changes in a signaling pathway called PI3K / AKT / mTOR. When there is a shortage of PPP2R2B, the HER2 targeted therapy seems unable to suppress the HER2 protein and the cancer spreads.

Using one drug to help another

Scientists discovered that another enzyme, EZH2 (enhancer of zest homolog 2), was responsible for suppressing the activity of PPP2R2B. They found that a clinically available drug called EPZ-6348 is able to block EZH2 activity, allowing both PPP2R2B and anti-HER2 drugs to resume their work of suppressing cancer.

Professor Lee, who is also chief and senior consultant in the Department of Hematology-Oncology at NCIS, said: “HER2 + breast cancer accounts for 20-25% of all breast cancers. It is highly dependent on HER2 signaling and is traditionally treated with drugs. that specifically target HER2.

Despite the initial efficacy, resistance to anti-HER2 therapy almost invariably develops in patients with advanced cancer, and they will eventually succumb to the disease. This study helps to understand why anti-HER2 drugs ultimately fail and offers a solution to restore sensitivity to anti-HER2 therapy, which may prolong patient survival.

The study discovered a new way in which cancer cells develop resistance to anti-HER2 drugs. Since one-third of HER2 and breast cancer cells have low levels of PPP2R2B, we predict that these cancer patients could benefit from adding an EZH2 inhibitor to anti-HER2 therapy. “

Yu Qiang, Professor and Principal Group Leader, Genome Institute of Singapore

The results were published in the journal Nature communications in November 2020.

Next steps

In the future, the research team plans to conduct a clinical trial to test the effectiveness of combining a drug that inhibits EZH2 with a standard anti-HER2 drug for the treatment of HER2 + breast cancer. They are also evaluating PPP2R2B as a potential predictive marker to select patients for anti-HER2 treatment.