Why Targeted Drug Doesn't Benefit Patients With Early-Stage Lung Cancer

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The drug erlotinib is highly effective in treating advanced-stage lung cancer patients whose tumors have a particular gene change, but when the same drug is used for patients with early-stage tumors with the same gene change, they actually fare worse than if they took nothing. A new study published in the journal Cancer Research might show why.
Oncologists use erlotinib to treat lung cancers that have a mutation in a gene called epidermal growth factor receptor (EGFR). The gene mutation causes EGFR to run like it has a stuck accelerator, and erlotinib blocks the overactive molecule. The study shows that while erlotinib effectively causes tumors to shrink, suggesting that the drug is helping, this drug also increases the aggressiveness of the tumor 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 called Notch3. Activation of that pathway leads to increased development of cancer stem cells among the surviving tumor cells and to accelerated tumor growth.
The findings might explain why erlotinib in clinical trials seems to worsen survival in patients with early-stage lung cancer. The researchers also suggest that combining an EGFR inhibitor with a Notch inhibitor should overcome the effect.

The study's key technical findings include:
- In two non-small-cell lung cancer cell lines, erlotinib treatment killed 84 percent and 75 percent of cells; of the surviving cells, 23 percent and 70 percent were stem-like cells, respectively (versus 4 percent and 18 percent 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.