Metastatic cancers: Protein that fuels treatment resistant tumours may be key to better outcomes

One of the biggest challenges in cancer treatment is addressing the ability of cancer cells to adapt and become resistant, reducing the effectiveness of therapies over time. While treatments like chemotherapy or targeted therapies may initially shrink tumours, they often lose their effectiveness after a period. This resistance often emerges in metastatic tumours, because cancer cells can evolve in ways that allow them to survive, such as developing new ways to communicate with one another.

Seeking ways to help patients whose cancers no longer respond to treatment, a team from the Yong Loo Lin School of Medicine, National University of Singapore (NUS Medicine), researched how tiny particles released by cancer cells, known as tumour-derived extracellular vesicles (TDEs), communicate with surrounding cells and induce resistance in cancer cells. Led by Professor Goh Boon Cher, Deputy Director of the NUS Centre for Cancer Research (N2CR) at NUS Medicine, and Professor Shazib Pervaiz who is also from the N2CR, the team found that blocking a certain protein, SLC1A5, led to more effective treatment of lung cancer.

Prof Goh said, “The discovery offers a new way to tackle one of the biggest challenges in  cancer treatment: resistance to therapy. By targeting the proteins which make it easier for cancer cells to survive when treatments are trying to kill them, doctors could improve existing treatments and create more personalised approaches for patients whose cancers have stopped responding.” Prof Goh is also Deputy Director of the Cancer Science Institute of Singapore (CSI Singapore) at NUS and a Senior Consultant in the Department of Haematology-Oncology at the National University Cancer Institute, Singapore (NCIS).

Published in the journal Theranostics, the study involved the use of 161 plasma samples, obtained from 103 patients with lung cancer of different stages, and 58 healthy individuals from the National University Hospital and NCIS. TDEs were isolated from these plasma samples, and their protein levels were analysed in the laboratory. Results showed that SLC1A5 levels are significantly higher in late-stage treatment-resistant tumours from the plasma samples of 62 patients, compared to early-stage sensitive tumours, with a p-value of less than 0.0001. These indicate that high levels of this protein in TDEs are associated with increased resistance to cancer treatment.

The protein is also a glutamine transporter that helps move glutamine into cells, providing them with the nutrients needed for growth and energy, especially in rapidly dividing cancer cells. In the laboratory experiments where the protein was blocked using pharmacological inhibitors or silencing SLC1A5 in the TDEs, treatment of the cancer cells was found to be significantly more effective. The experiments, led by Assistant Professor Eliza Fong, a collaborator from CSI Singapore, The N.1 Institute for Health, and Department of Biomedical Engineering under the College of Design and Engineering at NUS, showed that tumours resistant to treatment exhibit elevated levels of SLC1A5. As glutamine fuels cancer cells with energy, enabling their growth and resistance to treatment, blocking its intake can enhance the
effectiveness of cancer treatments.

Prof Pervaiz added, “Our study highlights how tumour-derived extracellular vesicles contribute to cancer drug resistance by transferring proteins like SLC1A5, which alter energy use in cancer cells, making them harder to treat. By breaking the communication network through blocking SLC1A5, we could help patients regain the benefits of therapy—and potentially increase chances of recovery from cancer.”

SLC1A5 levels could thus be used as a potential biomarker to detect resistance early and guide treatment decisions, added the study’s first author, Dr Jayshree Hirpara from CSI Singapore. “We also hope to understand better how tumour-derived extracellular vesicles and the SLC1A5 protein affect different cancer types, to provide new insights for more effective treatments. Having this mechanism in place, we need to develop treatments to overcome the transfer of SLC1A5 in the laboratory before considering clinical trials.”