Drug that reverses resistance to chemotherapy identified

WASHINGTON - Researchers have for the first time shown that inhibiting the action of an enzyme called TAK-1 could make pancreatic cancer cells sensitive to chemotherapy, paving the way for the development of a new drug to treat the disease.

Dr. Davide Melisi said that resistance to chemotherapy was the greatest challenge to treating pancreatic cancer.

“Pancreatic cancer is an incurable malignancy, resistant to every anti-cancer treatment. Targeting TAK-1 could be a strategy to revert this resistance, increasing the efficacy of chemotherapy,” said Melisi.

“During the past few years we have been studying the role played by a cytokine or regulatory protein called Transforming Growth Factor beta (TGFbeta) in the development of pancreatic cancer. Recently we focused our attention on a unique enzyme activated by TGFbeta, TAK-1, as a mediator for this extreme drug resistance,” he added.

For the study, the researchers investigated the expression of TAK-1 (TGFbeta-Activated Kinase-1) in pancreatic cell lines and developed a drug that was capable of inhibiting TAK-1.

They tested the activity of the TAK-1 inhibitor on its own and in combination with the anti-cancer drugs gemcitabine, oxaliplatin and SN-38 (a metabolite of the anti-cancer drug irinotecan) in cell lines, and the activity of the TAK-1 inhibitor combined with gemcitabine against pancreatic cancer in mice.

“The use of this TAK-1 inhibitor increased the sensitivity of pancreatic cells to all three chemotherapeutic drugs. By combining it with classic anti-cancer drugs, we were able to use doses of drugs up to 70 times lower in comparison with the control to kill the same number of cancer cells. In mice, we were able to reduce significantly the tumour volume, to prolong the mice survival, and to reduce the toxicity by combining the TAK-1 inhibitor with very low doses of a classic chemotherapeutic drug, gemcitabine, that would have been ineffective otherwise,” said Melisi.

The use of gemcitabine on its own against the cancer in mice was ineffective because of the drug resistant nature of the disease.

However, once it was combined with the TAK-1 inhibitor, the researchers saw a 78 percent reduction in tumour volumes.

“The median average survival for the control, TAK-1 inhibitor, gemcitabine on its own, or TAK-1 inhibitor combined with gemcitabine was 68, 87, 82 and 122 days respectively,” he said.

“This is the first time that TAK-1 has been indicated as a relevant target for the treatment of a solid tumour and that it is a valid approach to reverting the intrinsic drug resistance of pancreatic cancer,” he added.

The study was presented at Europe’s largest cancer congress, ECCO 15 - ESMO 34 in Berlin. (ANI)