By targeting small regulatory molecules called microRNAs (miRNAs), researchers were able to reprogram breast cancer cells and render them sensitive to HER2-targeting medicines, such as Herceptin (trastuzumab) and Kadcyla (ado-trastuzumab emtansine), a study shows.
The study, “A Designed Small Molecule Inhibitor of a Non-Coding RNA Sensitizes HER2 Negative Cancers to Herceptin,” was published in the Journal of the American Chemical Society.
About a fifth of breast cancers are driven by the protein HER2. This protein acts to send signals that drive excessive cell growth, and is associated with more aggressive cancers.
Breast cancers are often divided into HER2-positive and HER2-negative. For the former, treatments such as Herceptin — an antibody that targets and inhibits HER2 — and Kadcyla — the same as Herceptin but bound to a toxic payload — can be life-saving. But HER2-negative cases require other treatment options.
Whether a patient will respond to HER2-targeted treatments has long been thought to be an immutable property of tumors, but the new study suggests this might not be the case for future patients.
The researchers at The Scripps Research Institute, in Florida, were initially interested in using medications to target miRNAs. Unlike the more familiar messenger RNA — which takes the code from the genomic DNA in the cell nucleus to the protein-making machinery outside — miRNAs don’t encode for a protein product. Instead, they are involved in regulating other processes in the cell, acting in interconnected ways that are only beginning to be understood.
The investigators were particularly interested in a particular miRNA called miRNA-515, which is involved in regulating a few cancer-associated pathways. Some of these pathways, in turn, control the expression of HER2. Using a mathematical program called Inforna, the team designed and created a molecule to specifically target this miRNA.
Cancer cell lines treated with this experimental compound displayed a number of molecular and biological changes. For example, treated cells were more mobile and the expression levels of a number of proteins, including HER2, were also affected.
Based on this increased HER2 expression, the researchers predicted that their compound might make these cells more sensitive to Herceptin and Kadcyla treatment.
In three cell lines that are typically insensitive to HER2-targeted approaches, treatment with the experimental compound plus Herceptin or Kadcyla led to dramatically more cell death than Herceptin or Kadcyla alone.
As a proof of concept, this study shows that the genes a tumor expressed upon presentation — and what therapies might be beneficial for that patient — might be more malleable than previously thought.
“This study has implications for broadening the therapeutic utility of known targeted cancer therapeutics by using a secondary targeted approach to render otherwise insensitive cells sensitive to a targeted therapeutic,” investigators said.
“It’s possible that precision medicines like Herceptin can be made available to a wider group of people by altering gene expression with therapeutics that bind not to the proteins, but to noncoding RNA,” Matthew Disney, co-author of the study, said in a press release. “This means that supposedly untreatable diseases may one day be readily treatable. There is a long way to go for this to get to patients, however.”