By Dr Khor Ing Wei 

Dean's Office 

Cells use nutrients such as glucose, amino acids and fat (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.

 

A team of researchers at the Cancer Science Institute of Singapore (CSI) and Beth Israel Deaconess Medical Center in the U.S., led by Dr Azhar Ali, has 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.

 

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.1 A large majority of lung cancers (85%) are known as non-small cell lung cancers (NSCLC). A significant proportion of NSCLC patients (ranging from 10%-15% in Europe and the U.S., to more than 40% in Asia) have alterations (or mutations) in the epidermal growth factor receptor (EGFR) gene.2 Currently, the most effective treatment for this type of NSCLC are TKIs that specifically target the altered EGFR, with an overall survival of 2 to 4 years.3-5 However, over time, resistance to TKIs develops. At that point, patients have very limited 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 to this type of lung cancer have already been described. As discussed in their article in the February 2018 issue of the prestigious journal EMBO Molecular Medicine, Dr Azhar Ali, Dr Chin Tan Min, Professor Daniel Tenen 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.6 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, without palmitate, EGFR can no longer be modified by 

palmitate and is degraded 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.

 

Says Dr Azhar, "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 tumours that are driven by FASN and resistant to TKI drugs."

 

References

 

1. Lung Cancer: Estimated Incidence, Mortality and Preva lence Worldwide in 2012. GLOBOCAN 2012. http://globo can.iarc.fr/Pages/fact_sheets_cancer.aspx?cancer=lung.

2. Midha A, Dearden S, McCormack R. EGFR mutation incidence in non-small-cell lung cancer of adenocarcinoma histology: a systematic review and global map by ethnicity (mutMapII)Am J Cancer Res. 2015;5:2892-2911.

3. Inoue A, Koayashi K, Maemondo M, et al. Characteristics and overall survival of EGFR mutation-positive non-small cell lung cancer treated with EGFR tyrosine kinase inhibitors: a retrospective analysis for 1660 Japanese patients. Ann Oncol. 2013;24:54-59.

4. Yamamoto N, Goto K, Nishio M, et al. Int J Clin Oncol. 2017;22:70-78.

5. Kato T, Yoshioka H, Okamoto I, et al. Afatinib versus cisplatin plus pemetrexed in Japanese patients with advanced non-small cell lung cancer harboring activating EGFR mutations: subgroup analysis of LUX-Lung 3.Cancer Sci. 2015;106:1202-1211.

6. Ali A, Levantini E, Teo Jt, et al. Fatty acid synthase mediates EGFR palmitoylation in EGFR mutated non-small cell lung cancer. EMBO Mol Med. 2018 Feb 15. [Epub ahead of print].

Left: The authors found a new mechanism by which some lung cancers develop resistance to tyrosine kinase inhibitors (TKI) drugs. They found that an enzyme in fat synthesis, fatty acid synthase (FASN), is key to the process. FASN facilitates the production of the fatty acid palmitate, which modifies the mutated EGFR protein on some lung cancer cells, making them resistant to TKIs such as gefitinib. Blocking FASN with the drug Orlistat wipes out the production of palmitate, making the cancer cells susceptible to gefitinib and stunting their growth.