Potential new target for halting cancer growth

Research that builds on more than three decades of work at the Walter and Eliza Hall Institute (WEHI) in Melbourne has discovered that lymphomas that have high levels of the cancer-causing protein c-MYC cannot survive long term without a protein called MCL-1.

Dr Gemma Kelly, Dr Marco Herold and Professor Andreas Strasser, from the Molecular Genetics of Cancer division, have led a research team investigating how cells with high levels of MYC stay alive and grow. How MYC drives cancer development and how the survival of normal and cancerous cells is regulated has been the subject of research at the WEHI for decades.

c-MYC is a transcriptional regulator that is abnormally overexpressed in up to 70% of human cancers, including many leukaemias and lymphomas. These unusually high levels of MYC cause cancerous changes in cells by forcing them into abnormally rapid growth.

“For many years we have known that proteins from the BCL-2 protein family enhance cell survival and cooperate with MYC to accelerate the development of cancer,” Dr Kelly said, explaining that evading apoptosis is critical for cancer development, particularly in c-MYC-driven cancers. “Until now, it was not known which specific anti-apoptotic BCL-2 family protein was most important for the survival and growth of MYC-driven cancers.”

“We discovered that lymphoma cells with high levels of MYC can be killed by disabling a protein called MCL-1. Excitingly, when compared with healthy cells, the lymphoma cells were considerably more sensitive to a reduction in MCL-1 function.

“This suggests that in the future medicines that block MCL-1 could be effective in treating cancers expressing high levels of MYC with tolerable side effects on the body’s normal cells,” she said.

Professor Strasser said the finding was exciting because there was hope that MCL-1 inhibitors may soon be available for clinical use.

“MCL-1 is found at high levels in a number of blood cancers and also many solid tumours, so there has been a strong drive to develop potential anti-cancer compounds that target MCL-1,” he said.

“Anti-cancer agents that target the protein BCL-2, which is closely related to MCL-1, are already showing promise in clinical trials, including some held in Melbourne. We are hopeful that inhibitors of MCL-1 will soon become available for clinical testing. We will be very interested in determining whether these compounds could be used to treat MYC-driven cancers,” Professor Strasser said.

The research was published in the journal Genes & Development.