A ribbon diagram of EGFR in complex with its ligand EGF. Source: RCSB PDB (www.pdb.org) of PDB ID 1nql (Ferguson, K.M., Berger, M.B., Mendrola, J.M., Cho, H., Leahy, D.J., and Lemmon, M.A. (2003). EGF activates its receptor by removing interactions that auto-inhibit ectodomain dimerization Mol. Cell. 11: 507-517).
Researchers at the University of Texas identified genetic mutations in the EGFR signaling pathway as a probable mechanism of initiation for a substantial percentage of cancers (1). This discovery has numerous applications and could lead to new modes of chemotherapy for lung cancers (2).
Epidermal growth factor receptor (EGFR) is a cell-surface receptor that acts as a kinase, regulating the activity of other proteins (mTOR and Akt) in its pathway via phosphorylation (2). Some of these proteins regulated by EGFR are involved in autophagy, where the cell selectively destroys pieces of itself to either survive or intentionally kill itself. Autophagy has been closely linked to many cancers, and because of this, EGFR is known as an oncogene.
To establish oncogenic EGFR signaling’s relationship with cellular autophagy, the team measured its interaction with the protein Beclin 1, which is regulated by Akt, and is active in cellular autophagy (3). When Akt is mutated, it can inactivate Beclin 1, which has been linked to tumor initiation (3).
The team decided to investigate a possible link between EGFR and Beclin 1 via fluorescence microscopy (2). They were able to determine that the two proteins did interact and, after further investigation, were also able to establish that mutant EGFR became more active than the wild type receptor, and inhibited autophagy via its constant interaction with Beclin 1 (2).
After establishing the link between EGFR, Beclin 1, and autophagy, the researchers decided to turn their eye to EGFR’s troubling ability to adapt to chemotherapy. In EGFR-targeted methods of chemotherapy, erlotinib is given in order to block signaling pathways that contribute to tumor cell division (4). However, cancers that initially respond well to erlotinib often develop resistance, causing a drop in positive patient outcomes (2).
To find out how some lung cancers can adapt to treatment, the team looked again at autophagy. In examining the relationship between erlotinib and autophagy, the researchers found that inhibition of autophagy in tumors expressing mutations in EGFR can increase their resistance to erlotinib, and that the use of autophagy inhibitors in these tumors can lead to poorer clinical outcomes (2).
This project was able to provide a wealth of information, showing the mechanism by which a common form of cancer arises and survives, and linking it to clinical outcomes. This could lead to more efficient forms of chemotherapy, and hopefully decreased patient mortality.
References:
- R.K. Amaravadi, et al. Clin Cancer Res. 17; 654 (2011).
- Y. Wei, et al., Cell. 154; 1269-1284 (2013).
- R. Kang, H.J. Zeh, M.T. Lotze, D. Tang. Cell Death Differ. 18; 571-580 (2011).
- Erlotinib. (2009). Available at http://www.nlm.nih.gov/medlineplus/druginfo/meds/a605008.html (27 September 2013)