Battling cancer treatment resistance in relapsed acute myeloid leukaemia

A team of scientists, led by Assistant Professor Shruti Bhatt from the NUS Department of Pharmacy and Pharmaceutical Sciences, has uncovered evasion of apoptosis as a key driving mechanism that causes resistance to treatment in an aggressive form of blood cancer called acute myeloid leukaemia (AML). By targeting the mechanism of acquired resistance, results obtained from this study are expected to contribute towards the identification of effective drugs for treating relapsed AML patients.

In most cases, oncologists see dramatic response and reduced tumour burden after cancer patients go through their first line of treatment whether it be chemotherapy or targeted therapy. However, for many patients, there is a risk that the tumour comes back after successful treatment. When cancer comes back, it is often more aggressive and harder to treat. The reason behind this is that the cells that come back have not only become resistant to the treatment that a patient has received but also to multiple other agents through a phenomenon called acquired multi-drug resistance. This inability to eradicate cancer cells at relapse is a major cause of treatment failures. Beyond genetic mutations, biological evidence to explain the emergence of multi-drug resistance is lacking.

Asst Prof Bhatt and her research team identified reduced mitochondrial priming as a potential mechanism behind multi-drug resistance in relapsed AML patients. Mitochondrial priming refers to a cell’s threshold for apoptosis. Cells with highly-primed mitochondria stand ready to activate apoptosis and are more vulnerable to cancer therapies. "The findings from this study suggest that when AML becomes resistant to one therapeutic, its threshold for cell death increases—meaning that it becomes less likely to succumb to any cytotoxic therapy, whether or not the cell has been previously exposed to it,” said Asst Prof Bhatt.  

The researchers also highlighted the effectiveness of a technique, called dynamic BH3 profiling (DBP), in identifying anti-cancer drugs capable of targeting relapsed leukaemia cells. The technique can measure the increase in mitochondrial priming, which signifies a higher potential for programmed cell death called apoptosis. “One way to battle multi-drug resistance is to develop broadly effective predictive biomarkers to identify drugs with new or persistent activity in resistant tumours. DBP's ability to effectively identify exploitable vulnerabilities paves the way for the development of targeted in vivo therapeutic strategies”, added Asst Prof Bhatt.

The research was conducted in collaboration with Dr Anthony Letai from the Dana-Farber Cancer Institute, United States of America. The research findings were published in the Blood Cancer Discovery, a journal of the American Association for Cancer Research, on 4 March 2024. Asst Prof Bhatt acknowledges funding support from the National Medical Council Research and American Society of Haematology as well as the efforts of her students.

Leukaemia research breakthroughs like Asst Prof Bhatt’s laboratory research are incredibly exciting because they mark the beginning of a new era to overcome cancer therapy resistance that is responsible for most deaths caused by cancer.

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