A new study led by the Garvan Institute of Medical Research reveals that cancer cells have an innate randomness in their ability to respond to chemotherapy, adding to their arsenal of evading treatment. The work shows that tumour cells from neuroblastoma, cancer that develops in the body’s “fight or flight” sympathetic nervous system, can switch between responding to chemotherapy and not.
Understanding why some tumour cells resist chemotherapy is a key challenge in cancer research, as chemotherapy remains a first-line treatment for most cancers.
“We showed there is ‘noise’ in the process of cell death, which is what happens to cancer cells with chemotherapy treatment, and that this inherent noise, or randomness, in the system of gene expression is an important aspect of chemoresistance,”
said Associate Professor David Croucher, Head of the Network Biology Lab at Garvan.
Treatment Window of Opportunity
Chemotherapy does not work for about 15% of people with neuroblastoma.
“Our findings suggest that genetics don’t account for everything; other layers of regulation and other mechanisms of tumor progression can also underpin drug response, so we need to consider them,”
said co-lead author Dr. Sharissa Latham.
The researchers demonstrated that once neuroblastoma cells become resistant to chemotherapy, they cannot be reversed, implying that there is a small window of opportunity for treatment to work on a tumour cell before it becomes resistant.
“Combining chemotherapy with drugs that target this noise within tumours may have the best results as a first-line treatment after diagnosis before tumours lock into a state of resistance,”
said Croucher. The typical protocol for clinical trials in cancer, in which a new treatment is given to patients who have exhausted all other treatment options, is turned on its head.
Marker for Resistance
The researchers used mathematical modelling to reduce the gene expression “noise” signals in cell death pathways in neuroblastoma tumours. They then applied this to patient cell samples, looking at single cells en masse to visually isolate the cells that did not respond to treatment.
They discovered a resistance marker — a group of proteins involved in the cell death process known as apoptosis.
“We wanted to figure out what underlies that randomness. What is it about those cells, and can anything be manipulated to make them respond,”
said Dr. Latham.
The researchers identified specific classes of approved drugs – HDAC inhibitors – that could be used with chemotherapy to stabilize the expression of genes involved in cell death or alter the innate threshold that could tip a tumour cell into a resistant state. The next step is to move the project forward to a clinical trial.
- Hastings JF, Latham SL, Kamili A, Wheatley MS, Han JZR, Wong-Erasmus M, Phimmachanh M, Nobis M, Pantarelli C, Cadell AL, O’Donnell YEI, Leong KH, Lynn S, Geng FS, Cui L, Yan S, Achinger-Kawecka J, Stirzaker C, Norris MD, Haber M, Trahair TN, Speleman F, De Preter K, Cowley MJ, Bogdanovic O, Timpson P, Cox TR, Kolch W, Fletcher JI, Fey D, Croucher DR. Memory of stochastic single-cell apoptotic signaling promotes chemoresistance in neuroblastoma. Sci Adv. 2023 Mar 3;9(9):eabp8314. doi: 10.1126/sciadv.abp8314