Targeted Drug Ineffective in Treatment of Early Stage Lung Cancer

Patients with early stage tumors fare worse with erlotinib than if they take nothing.

A drug typically used to treat advanced stage lung cancer is not as effective in the treatment of early stage cancer, and a recent study may have uncovered why.

The drug erlotinib is highly effective in treating advanced stage lung cancer in patients whose tumors have a particular gene change, however, it actually causes worse results in patients with early stage lung cancer than if they took nothing at all.

Erlotinib is used to treat lung cancers that have a gene mutation called epidermal growth factor receptor (EGFR), as the drug blocks the overactive molecule and effectively causes tumors to shrink. But erlotinib also increases the aggressiveness of tumors and causes the growth to accelerate after therapy ends.

In a study published recently in the journal Cancer Research, researchers found the accelerated growth is due to the secondary and previously unknown effect caused by inhibiting EGFR.

"Our findings might explain why erlotinib in clinical trials seems to worsen survival in patients with early-stage lung cancer," co-corresponding author David Carbone, MD, PhD, said in a press release. "They also suggest that combining an EGFR inhibitor with a Notch inhibitor should overcome the effect."

When erlotinib blocks EGFR, researchers found that it activates a second signaling molecule called Notch3. When that pathway activates, it leads to the increased development of cancer stem cells with the surviving tumor cells, and causes accelerated tumor growth.

The study revealed that in 2 non-small-cell lung cancer cell lines, treatment with erlotinib killed 84% and 75% of cells. In the remaining cells, 23% and 70% were stem-like cells, respectively, compared with 4% and 18% of control cells.

Erlotinib treatment also increased the growth potential of surviving lung cancer cells and increased the number of stem-like cells through activation of the Notch3 receptor.

"We found that the activated, mutated EGFR directly inhibits Notch signaling, and that inhibiting EGFR with erlotinib removes this restraint and activates Notch signaling," Carbone said. "It suggests that specific dual targeting might overcome this adverse effect."