The drug erlotinib, which is effective in treating advanced-stage lung cancer patients whose tumors have a particular gene change, does not yield benefits for patients with early-stage tumors with the same gene change, according to a recent study from researchers at Ohio State University Wexner Medical Center.
Oncologists utilize this drug to treat lung cancers that have a mutation in a gene called epidermal growth factor receptor (EGFR), and erlotinib blocks the overactive molecule. The study finds that while erlotinib can cause tumors to shrink, but also increases the aggressiveness of the tumor so that growth is accelerated when therapy ends, researchers say.
The study determined that this is because of a secondary and previously unknown effect of inhibiting EGFR. The research team discovered that when erlotinib blocks EGFR, it activates a second signaling molecule called Notch3. This activation leads to increased development of cancer stem cells among the surviving tumor cells and to accelerate tumor growth, according to the Ohio State news release.
The technical findings of the study showed that erlotinib treatment increased the prospective for growth of surviving lung cancer cells and also increased the number of stem-like cells through activation of the Notch3 receptor. Also, in two non-small-cell lung cancer cell lines, erlotinib treatment killed 84% and 75% of cells, and of the surviving cells, 23% and 70% were stem-like cells, respectively.
David Carbone, MD, PhD, states, “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 adds, “Our findings might explain why erlotinib in clinical trials seems to worsen survival in patients with early-stage lung cancer. They also suggest that combining an EGFR inhibitor with a Notch inhibitor should overcome the effect.”
Source: Ohio State University Wexner Medical Center