Scientists discover new mechanism by which chronic lymphocytic leukaemia resists treatment

23. Oct. 2024

So far, the only known way of resistance to treatment in chronic lymphocytic leukaemia has been the development of genetic mutations in the DNA of the leukemic cell, allowing it to resist the treatment and continue to multiply. However, a research team from CEITEC Masaryk University (MUNI) and the University Hospital Brno discovered that chronic lymphocytic leukemic cells can resist the treatment by a non-genetic mechanism, i.e. without mutations. The essence of this non-genetic mechanism is the activation of a group of proteins that allow leukemic cells to survive the blockage of an important BCR signalling that plays a role in the survival of leukemic cells.

Chronic lymphocytic leukaemia (CLL) is the most common type of adult leukaemia and arises from white blood cells called B-lymphocytes. Normally, B-lymphocytes are formed in the bone marrow, then circulate in the blood and lymph nodes, where they participate in the body's defence against infections by producing antibodies. In CLL, however, B-lymphocytes proliferate pathologically and do not die, thus interfering with the healthy functioning of the immune system.

A decade ago, CLL treatment marked a breakthrough with introduction of targeted therapy with ibrutinib – an inhibitor (blocker) of the BTK protein involved in the so-called BCR signalling pathway – which enables B-lymphocytes to recognise foreign substances such as bacteria and viruses and subsequently trigger the body's immune response with antibody production. CLL patients have been shown to have abnormal activity of this BCR signalling pathway, which drugs such as ibrutinib block. This slows down the proliferation of cancer cells and limits their survival. BCR inhibitors can thus control the disease well and their introduction was a breakthrough in the treatment of these diseases but, unfortunately, even these drugs cannot completely eliminate leukaemia. Treatment must therefore be given continually over a long period of time, giving leukemic cells the opportunity to adapt and potentially build up resistance.

The genetic type of the resistance is already well documented – the way it works is that selected genetic changes in CLL cells prevent the drug from binding properly to the target molecule causing the drugs to stop working. Now, however, scientists have found that CLL cells can survive the treatment even without genetic mutations. The first such non-genetic mechanism has been described by a team from CEITEC MUNI and the University Hospital Brno led by Marek Mráz and their findings have been published in the prestigious journal The Journal of Clinical Investigation (JCI). The project was a collaboration between the National Institute for Cancer Research and scientists from Southampton, UK, and Harvard, USA. "We found that CLL cells in patients treated with BCR inhibitors activate an alternative signalling pathway leading to increased activity of the Akt protein, which helps CLL cells survive during treatment and eventually accumulate further mutations and acquire full resistance to the treatment," said Laura Ondrišová, a PhD student in Marek Mráz's research group and lead author of the study.

The activation of the Akt protein is mediated by the FoxO1 protein. The research shows that FoxO1 is an extremely important part of the early mechanism of adaptation to BCR inhibitor treatment, regardless of genetic changes. "Our results from preclinical testing of the FoxO1 inhibitor alone or in combination with BCR inhibitors revealed its potential for possible future use in CLL therapy," adds Marek Mráz.

Inhibition of FoxO1 activity together with BCR inhibition could effectively block the uncontrolled proliferation of leukemic cells. The FoxO1 inhibitor has also been tested in a mouse model and this strategy has a potential to be further validated in clinical testing.