EGFR Inhibitors May Induce Tumor Stemness

EGFR inhibitors such as erlotinib (Tarceva; Genentech/Astellas) and lapatinib (Tykerb; GlaxoSmithKline) generate drug-resistant cells that resemble cancer stem cells, researchers report in a new study (Nat Cell Biol 2014;16:457–68). They also uncovered the mechanism behind this conversion and propose a treatment approach that may counteract it and restore tumor cells' susceptibility.

A team led by David Cheresh, PhD, and Laetitia Seguin, PhD, of the University of California, San Diego, Moores Cancer Center in La Jolla, discovered that, with erlotinib treatment, tumor cells expressed the marker CD61, also known as integrin α_vβ₃. The presence of CD61 was enough to confer stem-cell attributes and drug resistance on the cells in vitro and in vivo, the researchers found. They implanted immune-deficient mice with tumor cells that either carried or lacked the β₃ integrin subunit. Only cells that harbored the subunit sustained tumor growth and remained resistant to erlotinib and lapatinib.

Clinical data supported these results. Biopsies from lung cancer patients whose disease had progressed on erlotinib showed higher levels of CD61 than did biopsies from patients who hadn't received the drug, Cheresh and colleagues described in the study.

Drugs such as EGFR inhibitors can induce metabolic stress in a tumor, prompting some tumor cells to adapt so they can survive. One of their responses is to upregulate CD61. “Tumor cells that exploit this mechanism become very stem-like,” says Cheresh. “Moreover, these CD61-expressing cells are particularly dangerous, as they tend to metastasize to a greater degree” than do cells lacking the marker, he says.

By tracing the molecular chain of events inside the stem-like cells, the researchers uncovered a way to switch them back. They found that CD61 interacts with KRAS and RalB at the plasma membrane, resulting in increased activation of TBK1 and NF-κB. Cells require this pathway to take on stem-cell characteristics and become drug resistant.

Drugs that disrupt the NF-κB pathway are available, including bortezomib (Velcade, Millennium), a treatment for multiple myeloma that hasn't proven effective for solid tumors. However, Cheresh and colleagues showed that the combination of erlotinib and bortezomib curtailed lung tumor growth in mice and eliminated the CD61-expressing cells from the tumors. “We could revert the cells to a more drug-sensitive state,” he says.

Later this year, a team led by Hatim Husain, MD, at the Moores Cancer Center will test Cheresh and Seguin's model of tumor drug resistance in the clinic. Patients who develop resistance to erlotinib will be given the combination of bortezomib and erlotinib with the hope that the tumors will respond just as they did in mice.

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