Editors' ChoiceMEDICINE

Targeting EGFR fusions in lung cancer

Sci. Signal.  14 Jun 2016:
Vol. 9, Issue 432, pp. ec138
DOI: 10.1126/scisignal.aag3308

Patients with tumors harboring activating mutations in the kinase domain of epidermal growth factor receptor (EGFR) are selected for treatment with tyrosine kinase inhibitor (TKI) therapy. Using next-generation sequencing, Konduri et al. identified EGFR fusions in some patients with metastatic lung adenocarcinoma that conferred activation of EGFR signaling and sensitivity to TKIs (see also Paik). The most common fusion was between the intact tyrosine kinase domain of EGFR and the DNA damage response protein RAD51. In NR6 mouse fibroblast-derived cells (which lack endogenous EGFR) and Ba/F3 mouse pro B cells, expressing the EGFR-RAD51 fusion protein activated downstream signaling through the mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) pathways and promoted colony growth in agar. Although the EGFR-RAD51 fusion protein lacked binding sites for signaling adaptor proteins, it contained the critical functional residue Tyr845 in the activation segment of the kinase domain. Because it also lacked binding sites for the E3 ubiquitin ligase CBL, the EGFR-RAD51 fusion protein could not be marked for degradation; in accord, EGFR-RAD51 fusion protein was more stable than wild-type EGFR. Structural modeling predicted that the self-assembling filamentous nature of RAD51 might enable dimerization of EGFR, enabling it to signal independently of ligand-triggered activation. The other EGFR fusion protein detected was that with the single-stranded DNA-binding protein PURβ, which is implicated in the regulation of DNA replication and transcription and can also self-dimerize. Treating Ba/F3 cells expressing these EGFR fusions with erlotinib, cetuximab, and other TKIs suppressed cell proliferation and MAPK and PI3K pathway activity. Patients in this study showed at least an initial response to erlotinib, with a few showing disease progression again after months of therapy. The findings reveal a new mode of EGFR activation and indicate that patients with EGFR fusions—not just those with EGFR mutations—may benefit from TKI therapy. It will also be of interest to investigate whether the EGFR fusion disrupts the activity of its partners, PURβ or RAD51, conferring sensitivity to therapies exploiting aberrations in DNA damage response, replication, or transcription.

K. Konduri, J.-N. Gallant, Y. K. Chae, F. J. Giles, B. J. Gitlitz, K. Gowen, E. Ichihara, T. K. Owonikoko, V. Peddareddigari, S. S. Ramalingam, S. K. Reddy, B. Eaby-Sandy, T. Vavalà, A. Whiteley, H. Chen, Y. Yan, J. H. Sheehan, J. Meiler, D. Morosini, J. S. Ross, P. J. Stephens, V. A. Miller, S. M. Ali, C. M. Lovly, EGFR fusions as novel therapeutic targets in lung cancer. Cancer Discov. 6, 601–611 (2016). [PubMed]

P. K. Paik, Something old, something new, something borrowed, something fused: Novel EGFR rearrangements in lung adenocarcinomas. Cancer Discov. 6, 574–575 (2016). [PubMed]