Targeting survival protein may counter drug-resistance in non-Hodgkin lymphomas

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Targeting a cell survival protein could help treat some lymphomas, including those cancers with genetic defects that make them resistant to many existing therapies. This study was published in Blood (2014; doi:10.1182/blood-2014-09-601567).

Scientists from the Walter and Eliza Hall Institute in Melbourne, Australia, found that removing the pro-survival protein MCL-1 caused the death and elimination of lymphoma cells that had become resistant to conventional cancer treatments.

T-cell and B-cell lymphomas are types of white blood cell cancers known as non-Hodgkin lymphomas. T-cell lymphomas account for approximately 20% of non-Hodgkin lymphomas.

MCL-1 is a key regulator of programmed cell death (apoptosis), a process that, when disrupted, can cause cancer to develop and can also enable malignant cancer cells to survive abnormally well when exposed to anticancer treatments.

Half of all cancers become resistant to chemotherapy and radiotherapy by acquiring mutations in the tumor-suppressing p53 protein. Researcher Stephanie Grabow, PhD, said the research team discovered that MCL-1 helped these cancer cells to survive by subverting the normal process of apoptosis.

"There are several prosurvival proteins that promote the sustained survival of cancer cells; the challenge is to identify which one is the most important in keeping each type of cancer cell alive," Grabow said.

"When we removed MCL-1 in models of T-cell lymphoma that had lost the tumor suppressing protein p53, cancers could not develop, demonstrating that MCL-1 is critical for the development of T-cell lymphomas. Previous work from our colleagues at the institute has shown that MCL-1 is also critical for the survival and therapy-resistance of other blood cancers, including B-cell lymphoma and acute myeloid leukemia, indicating that is a very important target for potential new anticancer treatments."

Senior researcher Professor Andreas Strasser, PhD, said the finding reinforced the need to develop druglike compounds that specifically targeted MCL-1. "When cancers acquire mutations in p53, they become resistant to many conventional therapies," he said.

"Investigating the role of MCL-1 and other proteins involved in controlling apoptosis has shown that MCL-1 is a critical protein in the survival of many types of cancer cells. Targeting MCL-1 could therefore allow us to develop new, urgently needed therapies to treat cancers that have stopped responding to other anticancer drugs."

Grabow said the research team would continue to investigate the role of MCL-1 in the development and progression of other cancers, including other blood cell cancers and brain cancers. "Finding new treatment targets is crucial if we are to reduce the impact of these diseases," she said.

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