Examining Erlotinib

Study May Explain Why Targeted Drug Doesn’t Benefit Patients With Early-Stage Lung Cancer

David CarboneThe drug erlotinib is highly effective in treating advanced-stage 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 fare worse than if they had taken nothing at all.

A study by researchers at the OSUCCC – James and at Cincinnati Children’s Hospital might explain why.

Oncologists use erlotinib to treat lung cancers that have a mutation in a gene called epidermal growth factor receptor (EGFR). The mutation causes EGFR to run like it has a stuck accelerator, and erlotinib blocks the overactive molecule.

The study shows that while erlotinib causes tumors to shrink—suggesting that the drug is helping a patient—it also increases the aggressiveness of the tumor so that cancer-cell growth accelerates when therapy ends. The study found that this is due to a secondary and previously unknown effect of inhibiting EGFR.

The researchers discovered that when erlotinib blocks EGFR, it activates a second signaling molecule called Notch3. Activating that pathway leads to increased development of cancer stem cells among the surviving tumor cells and to accelerated tumor growth.

“Our findings might explain why erlotinib in clinical trials seems to worsen survival in patients with early-stage lung cancer,” says co-corresponding author David Carbone, MD, PhD, a professor in the Division of Medical Oncology at Ohio State and co-leader of the OSUCCC – James Translational Therapeutics Program.

Carbone, co-corresponding author Stacey Huppert of Cincinnati Children’s Hospital and their colleagues conducted the study using several cell lines of non-small-cell lung cancer to learn if inhibiting EGFR enhances the activity of the Notch signaling pathway.

“We found that the activated, mutated EGFR directly inhibits Notch signaling,” Carbone says. “Inhibiting EGFR with erlotinib removes this restraint and activates Notch signaling, which suggests that combining an EGFR inhibitor with a Notch inhibitor might overcome this adverse effect.”

Published in the journal Cancer Research.

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