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ERIC 2020 | Combating CLL treatment resistance with BCL-2 and kinase inhibitors

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Dimitar Efremov

Dimitar Efremov, MD, PhD, International Centre for Genetic Engineering and Biotechnology, Trieste, Italy, discusses how resistance to apoptosis is due to the expression of anti-apoptotic protein BCL-2. This prompted the development of BCL-2 inhibitors fro chronic lymphocytic leukemia (CLL) treatment. However, the response to BCL-2 inhibitors is only partly due to the cell’s interaction with the microenvironment. However, the signals from the microenvironment can be blocked by kinase inhibitors such as ibrutinib. Therefore, the use of BCL-2 inhibitors in combination with kinase inhibitors could be an effective treatment. This interview took place during the European Research Initiative on CLL (ERIC) International Virtual Meeting 2020.

Transcript (edited for clarity)

Intrinsic apoptosis mechanism in CLL is overexpression of the anti-apoptotic protein BCL-2. And this knowledge actually prompted the development of the BCL-2 inhibitor venetoclax which is a drug that selectively kills the leukemic cells and which actually is now ultimately used to treat patients with CLL. Although this drug induces responses in the majority of treated patients, in most cases this is only partial because most because most patients still have residual disease in the lymph nodes...

Intrinsic apoptosis mechanism in CLL is overexpression of the anti-apoptotic protein BCL-2. And this knowledge actually prompted the development of the BCL-2 inhibitor venetoclax which is a drug that selectively kills the leukemic cells and which actually is now ultimately used to treat patients with CLL. Although this drug induces responses in the majority of treated patients, in most cases this is only partial because most because most patients still have residual disease in the lymph nodes. And the reason why our patient’s [inaudible 00:00:45] cells have more resistance to venetoclax is because because beside leukemic cells primary disease microenvironment or viral signal that increase the expression of certain anti-apoptotic BCL family proteins such as BCL and MCL-1 which are not inhibited by venetoclax and which I can substitute for BCL-2. Following this, microenvironment of signals can be blocked by certain kinase inhibitors, such as ibrutinib which can then sensitize the leukemic cells to venetoclax and this knowledge has been exploited to develop the venetoclax and ibrutinib combination regimen which is a highly effective treatment for CLL which is currently being investigated, used in clinical studies.

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