Weight-loss drug could fight resistant lung cancer

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New research could pave the way for using versions of an existing drug to keep lung cancer cells from becoming drug-resistant.

Researchers have discovered that a key enzyme in lipid metabolism controls the response to a class of targeted drugs called tyrosine kinase inhibitors (TKIs) in lung cancer.

Cells use nutrients such as glucose, amino acids, and lipids to produce the energy to support the essential processes that keep them alive and functioning. Cancer cells, those ultimate survivors, have figured out a way to tweak their own metabolism to increase the supply of energy, allowing them to multiply uncontrollably. These altered metabolic pathways can serve as targets for new cancer therapies, according to the new research.

Lung cancer is the most common cancer in the world and the top cause of cancer deaths, accounting for one in five deaths from cancer. A large majority of lung cancers (85 percent) are known as non-small cell lung cancers (NSCLC). A significant proportion of NSCLC patients (10-15 percent in Europe and the US, and more than 40 percent in Asia) have gene alterations (or mutations) in the epidermal growth factor receptor (EGFR) gene.

Currently, the most effective treatment for this type of NSCLC are TKIs that specifically target the altered EGFR, with an overall survival of two to four years. However, over time, resistance to TKIs develops. At that point, patients have very few treatment options and a very poor prognosis.

Understanding how this inevitable resistance to TKIs develops is crucial to tackling the problem. Several different mechanisms for TKI resistance in this type of lung cancer have already been described.

Taking this understanding further, Ali Azhar, senior research scientist at Cancer Science Institute of Singapore (CSI) at the National University of Singapore, and colleagues discovered a completely new mechanism involving fatty acid synthase (FASN), a key enzyme in lipid synthesis that facilitates the production of the saturated fatty acid palmitate.

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When palmitate modifies mutated EGFR in the cancer cells, it affects the way these tumor cells behave, making them resistant to the effects of TKIs.

Orlistat is a weight loss drug that blocks FASN, thus preventing the production of palmitate. In resistant cells, palmitate can no longer modify EGFR, which degrades instead. Treatment with Orlistat stunted the growth of EGFR-mutated NSCLC cells in cell culture systems and preclinical models. These findings provide strong evidence of the importance of FASN in survival and growth of this common type of lung cancer.

The next step is to target FASN using a modified version of Orlistat, which is poorly distributed throughout the body when given orally. A more effective therapy that blocks FASN will serve as a valuable treatment option for NSCLC patients with EGFR mutations who have developed resistance to TKI drugs.

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“Identifying molecular targets that are responsible for the development of resistance to chemotherapy has important implications for treatment. Drugs that interfere with fatty acid synthesis may thus be useful in treating these lung tumors that are driven by FASN and resistant to TKI drugs,” says Azhar.

The research appears in EBMO.

Source: National University of Singapore