Jasmine Brown, a senior majoring in neuroscience at Washington University in St. Louis, characterized the ability of insSVD EGFR to send proliferative signals to the cell in the absence of dimerization.
Lung cancer is the leading cause of cancer deaths in the United States and worldwide. Chemotherapy is not curative for most advanced lung cancer patients, but targeted therapies may hold more promise. Targeted therapy blocks the growth of cancer cells by interfering with specific molecules, typically somatically altered and required for the proliferation and survival of these cells. One of the first successful targeted therapies was erlotinib, which targets mutated forms of the Epidermal Growth Factor Receptor (EGFR) in lung cancer.
The Broad is a special place, with intense collaboration among amazing scientists who are making huge advancements in science while supporting each other. In BSRP, I found myself supported by the entire community as they pushed me to reach my potential - as a scientist, communicator, critical thinker, and collaborator.EGFR is a transmembrane receptor that dimerizes upon binding to its ligand, EGF. Asymmetric dimerization of the intracellular domain is required for the activation of wild-type EGFR. When activated, it sends signals to the cell, leading to cell division. When EGFR is mutated, it can become continuously activated, leading to excessive cell proliferation and eventually, cancer. Erlotinib is effective against several forms of mutationally activated EGFR found in cancer patients, but has no activity against one class of mutation involving insertion of extra DNA in exon 20 (exon 20 insertions).
Here, we examine whether asymmetric dimerization is required for the activation of a representative EGFR exon 20 insertion, insSVD. In order to address this question, we studied the effects of mutations that prevent EGFR dimerization on EGFR insSVD activity. Interestingly, we found that different dimerization-preventing mutations have different effects on the activity of insSVD EGFR.
This project will help us better understand the mechanism by which these mutated receptors can lead to cancer, which may lead to more effective cancer therapies.
Project: Mechanism for activation of insertion SVD epidermal growth factor receptor
Mentors: Bethany Kaplan and Heidi Greulich, Cancer Program