Experimental Drug Shrinks Lung Tumors by Blocking Fatty Acid Synthesis

This process is controlled by the rate-limiting enzyme acetyl-CoA carboxylase (ACC). When the enzyme is active, the product, malonyl-CoA, is produced. This is a building block for new fatty acids and can inhibit the transfer of the fatty acyl group from acyl CoA to carnitine with carnitine acyltransferase, which inhibits the beta-oxidation of fatty acids in the mitochondria.

Investigators at the Salk Institute (La Jolla, CA, USA) examined the effects of the ACC inhibitor ND-646 - an allosteric inhibitor of the ACC enzymes ACC1 and ACC2 that prevents ACC subunit dimerization - together with developers of the drug at the biotechnology company Nimbus Therapeutics (Cambridge, MA, USA).

They reported in the September 19, 2016, online edition of the journal Nature Medicine that chronic ND-646 treatment of xenograft and genetically engineered mouse models of NSCLC inhibited tumor growth. When administered as a single agent or in combination with the standard-of-care drug carboplatin, ND-646 markedly suppressed lung tumor growth in mouse models of NSCLC. Simultaneous treatment with the pair of drugs caused shrinkage of 87% of tumors as compared to 50% with the standard treatment of carboplatin alone. Treatment with the two drugs did not seem to impair normal cells even as it dramatically slowed cancer growth.

"Cancer cells rewire their metabolism to support their rapid division," said senior author Dr. Reuben Shaw, a professor of molecular and cell biology at the Salk Institute. "Because cancer cells are more reliant on lipid synthesis activity than normal cells, we thought there might be subsets of cancers sensitive to a drug that could interrupt this vital metabolic process."

"This confirms that shutting down endogenous lipid synthesis could be beneficial in some cancers and that inhibitors of the ACC enzyme represent a feasible way to do it," said contributing author Dr. Rosana Kapeller, CSO at Nimbus Therapeutics. "We have taken a novel computational chemistry approach to designing high-potency allosteric inhibitors of this difficult enzyme, and we are very encouraged by the results."

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