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P1.05 - Poster Session 1 - Preclinical Models of Therapeutics/Imaging (ID 156)
- Event: WCLC 2013
- Type: Poster Session
- Track: Biology
- Presentations: 1
- Coordinates: 10/28/2013, 09:30 - 16:30, Exhibit Hall, Ground Level
P1.05-025 - EGFR blockade increases lung cancer stem cell-like cells by upregulation of Notch3 signaling. (ID 3487)
09:30 - 16:30 | Author(s): S. Huppert
Blockade of genetic driver alterations in cell signaling pathways such as the epidermal growth factor receptor (EGFR) have led to dramatic tumor responses in the metastatic setting. However, these agents have unexpectedly failed to improve outcomes in clinical trails of early stage (BR.19) and locally advanced (S0023) NSCLC. In fact, survival was significantly worse among patients receiving gefitinib in the S0023 trial, and trended to be worse in BR.19. While it is clear that EGFR TKIs can reduce the tumor bulk and improve symptoms in the metastatic setting, these results raise the possibility that EGFR inhibition might somehow stimulate tumor growth either directly or indirectly.
We studied the fractions and numbers of ALDH+ cells and activation of stemcell signaling pathways in two EGFR mutated cell lines treated with erlotinib.
Here, we report that treatment of EGFR-mutated lung cancer cell lines with erlotinib, while showing robust cell death, essentially increases the fraction and absolute number of ALDH+ clonogenic stem cell-like cells. This phenomenon can be abolished by inhibition of Notch3, while Notch1 inhibition has little effect or slightly increases ALDH+ cells. We demonstrate EGFR kinase activity-dependent coprecipitation of Notch and EGFR receptors and EGFR kinase dependent tyrosine phosphorylation of the Notch3 receptor. We further found that inhibition of EGFR activity leads to increased nuclear accumulation of gamma-secretase dependent Notch3 that correlates with the increase in ALDH+ cells.
These data suggest that while EGFR TKIs are very effective at debulking tumors in the metastatic setting, inhibition of EGFR paradoxically causes Notch activation and an increase in clonogenic stem cell-like cells. Therefore, curative-intent therapy may be best accomplished by dual targeting of EGFR and Notch3.