Targeting breast cancer cells that change and adapt to evade chemotherapy in order to survive and grow, could be a new way to treat the often deadly triple-negative breast cancer, according to TFRI-funded researchers at the Princess Margaret Cancer Centre in Toronto.
Triple-negative breast cancer accounts for 15 per cent to 20 per cent of all yearly diagnosed breast cancers, but is responsible for a large portion of breast cancer deaths because it is so aggressive, and is more likely to have spread to other parts of the body and recur after treatment.
A study published in Cancer Discovery (Sept 2020), and led by senior author Dr. Mathieu Lupien, discovered changes in metabolism and epigenetics between chemotherapy-resistant and chemotherapy-sensitive cells, illuminating a major shift in understanding of the mechanisms driving drug-resistance – with the potential to identify a new druggable target.
“Our discovery is transformative because we found that non-genetic changes drive chemotherapy resistance, and these can provide more precise and druggable targets,” says Dr. Lupien, Senior Scientist at the Princess Margaret. “We demonstrate that the metabolism of chemotherapy-resistant cells induces a unique epigenetic state that allows cells to thrive in the presence of chemotherapy.”
Traditionally, cancer has been characterized as a genetic disease, but increasingly scientists have come to realize that epigenetic abnormalities are in fact key in initiating tumour development.
Building on rapid advances showing just how extensive alterations are in the epigenetic machinery of a cancer cell, major laboratories around the world are vying to understand the intricate nature of these epigenetic abnormalities which – unlike genetic mutations - are potentially reversible.
Emerging field of epigenetics
This has given rise to an emerging and massive global field of epigenetic therapy which seeks to reverse or restore the cell to a normal state – making this one of the most novel and important therapeutic avenues of cancer research.
In the laboratory, Princess Margaret researchers used patient-derived triple-negative breast cancer cells to identify epigenetic changes between two groups of cells: those that are chemotherapy-resistant and those that are chemotherapy-sensitive.
They found that specific epigenetic differences in drug-resistant cells were triggered by the metabolic stress induced by chemotherapy.
Specifically, these epigenetic changes or abnormalities in the chemo-resistant cells block a cellular viral mimicry response – a mechanism that normally prevents growth when cells sense viral infections, and that is activated by chemotherapy.
“Unblocking this viral mimicry response in chemo-resistant cells with drugs was our primary goal,” says Dr. Lupien, “and we found that epigenetic therapy could unblock the viral mimicry response to complement chemotherapy in preclinical studies.”
Epigenetic Switch–Induced Viral Mimicry Evasion in Chemotherapy-Resistant Breast Cancer
Geneviève Deblois, Seyed Ali Madani Tonekaboni, Giacomo Grillo, Constanza Martinez, Yunchi Ingrid Kao, Felicia Tai, Ilias Ettayebi, Anne-Marie Fortier, Paul Savage, Alexandra N. Fedor, Xiaojing Liu, Paul Guilhamon, Evelyne Lima-Fernandes, Alex Murison, Hellen Kuasne, Wail Ba-alawi, David W. Cescon, Cheryl H. Arrowsmith, Daniel D. De Carvalho, Benjamin Haibe-Kains, Jason W. Locasale, Morag Park and Mathieu Lupien
This study was partially funded by a Terry Fox Program Project Grant to New era of precision medicine in triple-negative breast cancer