Improving treatments for lung cancers: New targets tankyrase and wnt
Funded in part by Uniting Against Lung Cancer, Dr. James DeGregori (University of Colorado, Denver) and collaborators have identified new targets to help improve patient responses to EGFR-targeted therapy, such as erlotinib (Tarceva) and gefitinib (Iressa).
Using a high-tech screening method, Dr. DeGregori and his team were able to identify a number of potential targets that were necessary for cancer cells to stay healthy when treated with EGFR-targeted drugs. His grant from UALC was aimed at validatating these targets, and testing inhibitors against these targets in preclinical models to improve responses to EGFR inhibitors.
Published today in Cancer Research, Dr. DeGregori and collaborators identified the Wnt signaling pathway as a survival mechanism used by cancer cells. This pathway is involved in growth and development, and is thought to play an important role in the maintenance of normal tisses, as well as potentially play a role in non-small cell lung cancer maintenance. While the wnt pathway has been an attractive target to fight cancer, until recently it has been very difficult to block with drugs.
After identifying the Wnt pathway as an important contributor to lung cancer's ability to withstand EGFR treatment, the team focused on two proteins that have been shown to activate the Wnt pathway: tankyrase 1 and 2. Genetically silencing or using small molecule inhibitors to block these proteins resulted in improved responses to EGFR inhibitors.
This research gives us preliminary data for further development of tankyrase inhibitors used in combination with EGFR inhibitors, potentially improving responses to treatment and hopefully delaying acquired resistance.
Casas-Selves M et. al., Tankyrase and the canonical Wnt pathway protect lung cancer cells from EGFR inhibition. Cancer Research. Published Online First June 27, 2012; doi: 10.1158/0008-5472.CAN-11-2848