Researchers determined that simultaneously targeting the BRD4 and LOXL2 proteins disrupts their interaction and inhibits the growth of triple-negative breast cancer cells.
Recent findings published in EMBO Molecular Medicine demonstrate that the simultaneous inhibition of 2 different proteins may be a new method of slowing the growth of triple-negative breast cancer. This form of breast cancer, which is aggressive and drug-resistant with poor prognosis, makes up approximately 15% of breast cancer cases. However, existing treatments are ineffective due to the cells lacking the receptors that breast cancer drugs target.
Prior research has shown that the enzyme LOXL2 can drive triple-negative breast cancer growth, leading researchers to complete analyses to assess the suitability of the enzyme as a biomarker for predicting treatment outcome. LOXL2 expression was found to only predict outcomes of drugs which target the protein BRD4, a driver of cancer. Further, researchers evaluated whether LOXL2 and BRD4 may be working together in promoting the growth of triple-negative breast cancer cells.
In addition, LOXL2 was found to interact with a version of BRD4 inside the nucleus, and researchers demonstrated that the interaction changes the gene expression, ultimately helping the growth of triple-negative breast cancer cells. The simultaneous inhibition of both proteins disrupted the interactions, slowing the growth of cancer in cell cultures in vitro and in 3 separate mouse models in vivo.
“Our deep dive into how triple-negative breast cancer cells grow at the molecular level have revealed a new mechanism which can be exploited for treatment purposes,” said lead study author Laura Reguant, PhD, postdoctoral researcher at the Centre for Genomic Regulation in Barcelona, in a press release. “It is exciting because a double strike strategy that targets both proteins could be combined with other treatments and transform triple-negative breast cancer from a disease with a very poor prognosis into one that is manageable.”
The findings, which have significant implications for an experimental class of drugs known as BET inhibitors, show promise in treating triple-negative breast cancer. BET inhibitors compromise the function of BRD4; however, they have failed to pass the clinical trial stage due to triple-negative breast cancer cells acquiring resistance.
The researchers note that the next challenge will involve finding safe and effective methods of targeting both proteins simultaneously. Combining existing inhibitors, such as LOXL2 inhibitors, is one potential method; however, the safety and efficacy of LOXL2 inhibitors in cancer treatment has yet to be explored.
“More work needs to be done before our findings will benefit patients, but any progress in understanding the mechanisms of this highly aggressive disease is good news,” said Sara Sdelci, PhD, principal investigator at the Centre for Genomic Regulation, in the press release. “As we continue to shed light on how triple-negative breast cancer grows, the health challenges it poses might be more tractable than we first thought.”
University of Southampton. ‘Double strike’ strategy slows growth of drug-resistant breast cancer. News release. November 8, 2023. Accessed November 8, 2023. https://www.eurekalert.org/news-releases/1005555