Inhibiting certain enzymes of the Kreb’s cycle in cancer cells could provide insights into New Targeted Treatments

In a new study published in the journal Nature today, scientists from CANCER RESEARCH UK have discovered that cancer cells can be destroyed by restricting a certain energy-generating pathway used by kidney cancer cells.

The energy needed for cell growth and division is obtained by a process called Kreb’s cycle (TCA cycle) involving a variety of enzymes. The absence of these enzymes brings the cell cycle to a complete halt resulting in cell death.
“Hereditary leiomyomatosis and renal cell cancer*” (HLRCC) is a rare genetic condition that advances into a very aggressive form of kidney cancer. In HLRCC, kidney cancer cells exhibit survival despite the absence of one of the enzymes of the TCA cycle: Fumarate Hydratase (FH).

Researchers discovered that the absence of this enzyme did not shut down the Kreb’s cycle. Instead, the cells switched to an alternate pathway involving the build up and break down of an important molecule and by-product of the TCA cycle called haem. Researchers targeted Fumarate Hydratase deficient cancer cells by restricting a key enzyme called Hem Oxygenase, rendering the normal kidney cells unaffected.

Lead researcher at Cancer Research UK’s Beatson Institute in Glasgow, Professor Eyal Gottlieb, said: “By using the latest chemistry and computer technologies we were able to look at every energy generating reaction taking place in the cell and predict the effect of blocking these pathways. Armed with this knowledge we now need to confirm our findings in HLRCC patients and ultimately develop targeted drugs that selectively kill kidney cancer cells.”

He added: “We also want to use our approach to find other pathways and expose weaknesses in cancer cells that could be exploited, suggesting a whole new range of drugs to kill cancer cells.”

Senior science information manager at Cancer Research UK, Dr Julie Sharp, said: “Ten years ago, Cancer Research UK scientists found that faults in the gene for Fumarate Hydratase lead to the condition HLRCC. These latest results show us that the adaptation that the cancer cells use to survive could also be exploited as a weakness, and potentially lead to the design of new treatments.”

She added: “Recent research has found that levels of Fumarate Hydratase are also reduced in other types of kidney cancer, suggesting that if they are using the same pathway to generate energy then a drug to block this process could be used to treat a wider range of people with kidney cancer.”

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