An article published in Science Signaling explains why some tumors treated with ErbB inhibitors are resistant to treatment. According to researchers from Massachusetts Institute of Technology, there is a protein called AXL that help cancer cells to escape the effects of ErbB inhibitors.
ErbBs are proteins (epithelial growth factor receptors, EGFR) present in cancer cells and responsible for the uncontrolled growth and division. Drugs targeting these proteins have been shown effective in the treatment of cancer; examples of these drugs are Iressa, which is used to treat lung cancer, and Herceptin which is useful in treating certain types of breast cancer. Doug Lauffenburger, the Ford Professor of Bioengineering, head of MIT’s Department of Biological Engineering, said that there are many drugs that target ErbBs, but they have their limitations. He added that a solution to prevent the emergence of resistance to treatment would be the use of a combination therapy consisting of drugs that target ErbBs and AXL.
In their study, the research team led by Lauffenburger wanted to discover the factors that cause cancer cells to become resistant to treatment with EGFR and other ErbB inhibitors. Therefore they developed Cancer Cell Line Encyclopedia, ie a dataset containing information on over 1,000 human cancer lines and their response to treatment. After a detailed analysis of these cell lines, the researchers found that the strongest marker for EGFR inhibitor resistance is EGFR paired with AXL receptor. It seems that this marker is present in many types of cancers such as cancer of the lung, breast and pancreas.
Lauffenburger believes that when therapy targets a single signaling pathway, then resistance is very likely to occur. He added that the only way is to combine multiple therapeutic targets and to consider the interacting networks. Laboratory experiments have shown that when EGFR is activated, AXL also activates. AXL then stimulates other additional signaling pathways that lead to growth, division and migration of cancer cells throughout the body.
Researchers also found that other members of the ErbB family, similar to EGFR, are associated with AXL, which indicates that inhibition of AXL can treat cancers that are dependent on ErbB2, such as some breast cancers. Previous studies have shown that triple-negative breast cancers (those cancers that lack the three most frequent markers: estrogen receptors, progesterone receptors and HER2 receptors) express high levels of AXL, and the the results of the study explain why treatment with EGFR inhibitors fails despite high EGFR levels.