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Receptor Tyrosine Kinase AXL May Mediate Nuclear Translocation of EGFR

Key Points

  • Cancers develop cetuximab resistance via several mechanisms: researchers found that resistant cells have become dependent on EGFR within the nucleus, where it activates growth and survival genes; they also found that AXL is overexpressed in resistant cells and activates EGFR even when cetuximab is trying to block the signal.
  • By manipulating the levels of AXL and other proteins in cells growing in the lab, the research team identified a new role for AXL in which it also regulates the trafficking of EGFR to the nucleus.

New research from the University of Wisconsin (UW) Carbone Cancer Center has clarified the mechanisms involved in a common growth pathway implicated in many solid tumor types and could lead to better outcomes for patients with head and neck, lung, and triple-negative breast cancer, particularly those resistant to common therapies. The findings were published by Brand et al in Science Signaling.

The class of proteins known as receptor tyrosine kinases are best studied for how they receive progrowth signals from outside the cell and transmit those signals internally, telling the cell to survive, divide, and spread. Receptor tyrosine kinases, which were thought to function only on the cell's surface, have more recently been found inside the cell's nucleus, where they turn on genes involved in tumor growth and survival.

“Nuclear localized [receptor tyrosine kinases] can mediate resistance to therapeutics used to treat cancer, such as radiation therapy, chemotherapy, or antibody-based therapies that directly block [receptor tyrosine kinases] on the cell surface,” said Toni Brand, PhD, a former UW Madison graduate student in Deric Wheeler, PhD’s lab and lead author of the study. “We wanted to identify how [receptor tyrosine kinases] move to the nucleus so that we can design therapies to block their transport and, hopefully, enhance the efficacy of antibody-based therapies in the future.”

To better understand how cells develop resistance to cancer therapies, Dr. Wheeler's group used cells that have developed resistance to the anti–epidermal growth factor receptor (EGFR) drug cetuximab (Erbitux). Cetuximab sticks to EGFR outside the cell and, if the cell has not developed resistance, blocks it from receiving and transmitting growth signals.

Cetuximab Resistance, EGFR, and AXL

In earlier studies, the researchers found that cancers develop cetuximab resistance via several mechanisms. First, they found that resistant cells have become dependent on EGFR within the nucleus, where it activates growth and survival genes. More recently, they found that another receptor tyrosine kinase, called AXL, is overexpressed in resistant cells and activates EGFR even when cetuximab is trying to block the signal.

“Based on our previous work identifying a role for both AXL and nuclear EGFR in cetuximab resistance, we wanted to determine if there was a molecular link between these two resistance pathways,” Dr. Brand said.

By manipulating the levels of AXL and other proteins in cells growing in the lab, the research team identified a new role for AXL in which it also regulates the trafficking of EGFR to the nucleus, suggesting that AXL could influence resistance to cetuximab by increasing the amount of EGFR in the nucleus.

“Not only does AXL regulate tumor growth pathways by functioning as a [receptor tyrosine kinase] on the cell surface, it also regulates the accumulation of EGFR and other [receptor tyrosine kinases] in the nucleus,” Dr. Brand said. “Our work provides a rationale for why we should therapeutically target AXL, because it plays a more diverse role in tumor biology than we originally thought.”

Though Dr. Wheeler’s group and others had already found a role for AXL in cancer, this new study provides important details as to how the protein regulates resistance to anticancer treatments. So while AXL-targeting therapies are currently in clinical trials, Dr. Wheeler explained that having a clear picture of how AXL drives resistance is critical in staying one step ahead.

“The current study is exciting because it identifies AXL as a key mediator of resistance pathways that, collectively with other studies, suggests that AXL may be a potent molecular target in resistant cells,” Dr. Wheeler said. “A story is beginning to emerge where we are understanding new and novel functions of [receptor tyrosine kinases] within the cell that can drive resistance to cancer therapies, and we hope this study can influence the clinical advancement of AXL inhibitors for the treatment of patients.”

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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