Mutations in the epidermal growth factor receptor (EGFR) are the most common actionable genetic abnormalities yet discovered in lung cancer. However, targeting these mutations with kinase inhibitors is not curative in advanced disease and has yet to demonstrate an impact on potentially curable, early-stage disease, with some data suggesting adverse outcomes.
The drug erlotinib is routinely used to treat advanced non-small cell lung cancers with a mutation in EGFR, but when the same drug is used for patients with early-stage tumours with mutation in the same gene, they actually fare worse. A study by researchers at The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC – James) and at Cincinnati Children’s Hospital might show why.
The study shows that while erlotinib effectively causes tumours to shrink, this drug also increases the aggressiveness of the tumour so that growth is accelerated when therapy ends. This study finds that this is due to a secondary and previously unknown effect of inhibiting EGFR.
The researchers found that when erlotinib blocks EGFR, it activates a second signaling molecule, Notch3. Activation of that pathway leads to increased development of cancer stem cells among the surviving tumour cells and to accelerated tumour growth.
“Our findings might explain why erlotinib in clinical trials seems to worsen survival in patients with early-stage lung cancer,” says one of corresponding authors Dr David Carbone, professor of medicine, Division of Medical Oncology at the OSUCCC – James. “They also suggest that combining an EGFR inhibitor with a Notch inhibitor should overcome the effect.”
The study was published in the journal Cancer Research.
Dr Carbone and colleagues conducted the study using several cell lines of non-small cell lung cancer. “We found that the activated, mutated EGFR directly inhibits Notch signaling, and that inhibiting EGFR with erlotinib removes this restraint and activates Notch signaling,” says Dr Carbone. “It suggests that specific dual targeting might overcome this adverse effect.”
In this study:
- In two non-small cell lung cancer cell lines, treatment with erlotinib killed 84% and 75% of cells; of the surviving cells, 23% and 70% were stem-like cells, respectively (versus 4% and 18% of control cells);
- Erlotinib treatment increased the potential for growth of surviving lung cancer cells;
- Erlotinib treatment increased the number of stem-like cells through activation of the Notch3 receptor.
This research was supported by funding from the USA NIH/National Cancer Institute (grant CA090949).