Combating resistance to EGFR-targeted therapies: New target AXL identified
Between 10-35% of patients with non small cell lung cancers have tumors harboring mutations to the epidermal growth factor receptor (EGFR). These patients usually respond to therapies targeting EGFR, such as the EGFR inhibitor erlotinib (Tarceva). However, these patients will eventually become resistant to EGFR inhibitors, leaving no effective treatment available. Funded in part by Uniting Against Lung Cancer, Dr. Trever Bivona and collaborators have identified the AXL kinase as a promising new drug target to overcome acquired resistance to EGFR inhibitors.
EGFR inhibitors block the activity of EGFR, preventing it from sending growth signals within the cell. Yet, cancer can find ways to bypass the effect of the drug, becoming resistant to treatment. Tumors can develop another mutation in EGFR (T790M) that causes it to become active even in the presence of the inhibitor. Tumors can also utilize other singaling pathways and proteins to compensate for EGFR inhibition, such at the MET kinase or activation of the NF-kB pathway. Dr. Bivona's grant from UALC was aimed at uncovering additional targets used by tumors to become resistant to EGFR inhibition.
In his recent publication in Nature Genetics, Dr. Bivona and his collaborators looked at EGFR-mutant preclinical models and clinical samples. They found that AXL was the most highly expressed gene in tumor models with acquired resistance. The team was able to restore tumor sensitivity to EGFR inhibitors by blocking AXL genetically or with targeted inhibitors. The researchers were able to validate their findings in patient samples, and found that AXL upregulation was second most common alteration in EGFR inihibitor-resistant tumors, behind the T790M mutation.
AXL can promote cell growth and has previously been associated with lung cancers, particularly with invasive behavior and metastatic disease. UALC funded Dr. Rachel Linger in 2008-2010 to investigate using AXL inhibitors in combination with chemotherapy as a treatment for lung cancers. Dr. Bivona's new data shows that AXL can play a pivotal role in resistance to EGFR inhibition, and may be associated with epithelial-to-mesenchymal transition (the early stages of metastasis).
This research lays the groundwork for clinical trials testing AXL inhibitors in NSCLC patients harboring EGFR-positive lung cancers with acquired resistance to EGFR inhibitors. Successful trials could provide a new therapy for patients who currently have no effective treatment options.
Zhang et al., Activation of the AXL kinase causes resistance to EGFR-targeted therapy in lung cancer. Nature Genetics. Published online July 1, 2012.