Amyn Habib, M.D.

By Julie Kirchem, Department of Neurology and Neurotherapeutics

Amyn Habib, M.D., Associate Professor of Neurology and Neurotherapeutics, and UT Southwestern colleagues have made a discovery into how an important target in cancer treatment functions to resist chemotherapy. The discovery, published in Nature Communications, could lead to new therapies for certain cancers.

The target is the epidermal growth factor receptor (EGFR) protein and is expressed at high levels in up to one third of human cancers including brain tumors (glioblastoma), lung, breast and head and neck cancers.

Dr. Habib’s lab discovered a new type of EGFR signaling in cancer cells that is called constitutive or non-canonical. This type of signaling is generated by the EGFR in cancer cells in the absence of ligand or partner molecule. Normally, the EGFR signals only when its ligand binds to it.

Increased EGFR signaling triggers survival and proliferation signals within tumor cells that lead to resistance to chemotherapy and other forms of treatment.

“The new signaling pathway discovered involves activation of a transcription factor called IRF3,” said Dr. Habib.  “Activation of IRF3 may execute EGFR-mediated resistance to chemotherapy, so IRF3 may be a new target for treatment in cancer.”

Previously, scientists believed that EGFR signaling in the absence or presence of ligand is similar, but Dr. Habib and his team of researchers have found that is not the case.

“The importance of our work stems from the finding that ligand-independent and ligand-dependent EGFR signaling in cancer cells is distinct and mutually exclusive,” said Dr. Habib.

“The next step for us is to examine the effect of IRF3 inhibition using a small molecule inhibitor in a preclinical model of cancer.

The research was supported by the National Institutes of Health, Department of Veterans Affairs, the William and Sylvia Zale Foundation and the Ethel Silvergold Philanthropic Fund of the Dallas Jewish Community Foundation, and by donations from Barbara F. Glick.

Other UT Southwestern researchers include Dr. Bruce Mickey, Professor and Vice Chairman of Neurological Surgery, Professor of Otolaryngology and Radiation Oncology, Director of the Annette Straus Center for Neuro-Oncology at UT Southwestern, and holder of the William Kemp Clark Chair of Neurological Surgery; Dr. Joachim Herz, Professor of Molecular Genetics, Neurology & Neurotherapeutics, Neuroscience and holder of the Thomas O. and Cinda Hicks Family Distinguished Chair in Alzheimer's Disease Research; David A. Boothman, Professor with the Simmons Cancer Center, Pharmacology, and Radiation Oncology, who holds the Robert B. and Virginia Payne Professorship in Oncology; Dr. Rhonda F. Souza, Professor of Internal Medicine, staff physician with the North Texas VA,  and a member of the Simmons Cancer Center; Dr. Kimmo Hatanpaa, Associate Professor of Pathology; postdoctoral researchers Li Li, Gao Guo; Peggy Vo, research assistant; former UT Southwestern postdoctoral researchers Dr. Sharmistha Chakraborty, first author, and  Dr. Vineshkumar Thidil Puliyappadamba, and researchers from the National Taiwan University in Taipei, Taiwan; Department of Molecular Genetics at the Cleveland Clinic; and the Methodist Research Institute in Houston.