Breast cancer is the most common cancer in women worldwide and the second most common cancer in general. Although it can now be treated with drugs, many of these drugs secretly stop working over time, causing relapse.
Now a team of researchers from the Singapore Cancer Science Institute (CSI Singapore) at the National University of Singapore (NUS), the Singapore Genome Institute (GIS) under the Agency for Science, Technology and Research (A * STAR) and the The National Cancer Institute The University of Singapore (NCIS), along with their international research colleagues in Denmark, have found out why this is happening.
There are often several molecular pathways that stimulate cancer growth, and most targeted therapies affect only one molecular pathway. Drug resistance often develops due to ‘rescue’ from the other cancer pathway that is not targeted by drug treatment. The researchers found a solution – to provide an additional drug that would control the second path.
The team, led by Professor Lee Soo Chin of CSI Singapore and NUS School of Medicine Yong Loo Lin and Professor Yu Qiang of 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. HER2-targeting drugs are effective against HER2-overexpressing breast cancer cells, but these drugs eventually become ineffective, and scientists didn’t know why.
Demonstrating breast cancer immunity to HER2 target therapy
The scientists used the existing data from a biochemical database and tumor samples from 29 patients enrolled in a clinical trial conducted at NCIS, to zero in on an enzyme substrate added. called PPP2R2B (serine / threonine-protein phosphatase 2A 55 kDa subunit B beta isoform regulator) appeared to be scarce in cancer cells when HER2-targeting drugs failed to work.
The research team found that PPP2R2B inhibits cancer by making chemical changes in a signaling pathway called PI3K / AKT / mTOR. When there is a deficiency of PPP2R2B, it seems that HER2-targeted treatment cannot suppress the HER2 protein, and the cancer will spread.
Using one drug to help another
The experts found that another enzyme, EZH2 (developer zeste homologue 2), was responsible for suppressing PPP2R2B activity. They found that a clinically available drug called EPZ-6348 is able to inhibit EZH2 activity, allowing both PPP2R2B and the anti-HER2 drugs to resume their activity in eliminate cancer.
Professor Lee who is also Head & Chief Consultant at the Department of Hematology-Oncology at NCIS, said, “HER2 + breast cancer accounts for 20 percent to 25 percent of all breast cancers. It highly dependent on HER2 markers and traditionally treated with drugs that specifically target HER2.
Despite initial efficacy, resistance to anti-HER2 therapy develops almost dramatically in patients with advanced cancer, and eventually accepts the disease. This study provides insights into why anti-HER2 drugs ultimately fail and offers a solution to restore susceptibility to anti-HER2 treatment, which may sustain patient survival. “
The study found a new way in which cancer cells develop resistance to HER2 drugs. Given that one-third of HER2 and breast cancer cells have low levels of PPP2R2B, we predict that these cancer patients may benefit from the addition of an EZH2 inhibitor to the treatment against HER2. “
Yu Qiang, Professor and Principal Group Director, Genome Institute in Singapore
The findings were published in the journal Nature Communication in November 2020.
The next steps
Moving forward, the research team plans to conduct a clinical trial to test the efficacy of combining an EZH2-inhibiting drug with a standard anti-HER2 drug for the treatment of HER2 + breast cancer. They are also evaluating PPP2R2B as a potential predictive indicator for selecting patients for anti-HER2 therapy.
Source:
National University of Singapore
Magazine Reference:
Bao, Y., et al. (2020) E2H2-mediated inactivation of PP2A provides resistance to HER2-targeted breast cancer treatment. Nature Communication. doi.org/10.1038/s41467-020-19704-x.