Potential combination therapy for triple-negative breast cancer

Utrecht scientists have clarified how a combination therapy against breast cancer kills the tumor cells. A combination therapy alters the action of several proteins at the same time and thereby tackles the tumor. In new research they uncover the mechanism behind a combination therapy against an aggressive form of breast cancer. They publish their findings in the February issue of Molecular & Cellular Proteomics.

The scientists did research on Triple-negative breast cancer (TNBC). This is an aggressive form of breast cancer with very limited therapeutic options and a poor prognosis. Despite extensive research, there is still no treatment for this form of breast cancer, and the development of a new therapy is therefore desperately needed. 

The research group recently showed that combined inhibition of two proteins in breast cancer cells (EGFR and ROCK) results in cell death, but the underlying mechanisms remain unclear. Using mass spectrometry, the scientists were now able to uncover the underlying mechanism.

Combination

The Utrecht researchers, in collaboration with researchers from the NKI, have mapped changes in the expression and activation of proteins in single and combined therapy. "Our research data revealed autophagy – the process by which cell products are broken down and reused – as the most important process in the response of breast cancer cells to the combined treatment", says last author Maarten Altelaar of Utrecht University.

The beneficial effect only occurred in the combined therapy. If the researchers only inhibited the EGFR protein with single therapy, a protective reaction for the tumor cells occurred. "Combined inhibition of the proteins EGFR ánd ROCK, however, leads to blockage of autophagy and therefore accumulation of the vesicles filled with material intended for recycling", says Altelaar. That ultimately leads to antitumor activity through cell death.

For a durable clinical response one needs to develop effective combinatorial strategies, Altelaar says, such as this combined EGFR-ROCK inhibition. “It opens up new opportunities for TNBC therapy.”

Diagnosis

Previously, these researchers were able to identify reliable biomarkers to specific breast cancer subtypes, such as TNBC, based on extracellular vesicles. "These vesicles are excreted by tumors in the bloodstream and after purification, the proteins present can be used for non-invasive diagnosis of breast cancer, so-called liquid biopsies", Altelaar explains.

Publication

Combined EGFR and ROCK inhibition in TNBC leads to cell death via impaired autophagic flux. Stamatia Rontogianni*, Sedef Iskit, Sander van Doorn*, Daniel S. Peeper and Maarten Altelaar*. Molecular & Cellular Proteomics, February issue. pii: mcp.RA119.001800. doi: 10.1074/mcp.RA119.001800.

* Authors affiliated with Utrecht University