Robert Lefkowitz, MD, and Brian Kobilka, MD, will share the 2012 Nobel Prize in Chemistry for their groundbreaking studies on G-protein-coupled receptors, a family of cell-surface molecules that play a role in tumor growth and metastasis and may lead to the development of more effective cancer drugs.

Robert Lefkowitz, MD, and his former fellow, Brian Kobilka, MD, share the 2012 Nobel Prize in Chemistry for their groundbreaking studies on G-protein-coupled receptors (GPCR), the largest family of membrane-bound proteins involved in signal transduction. The 2 researchers are scheduled to receive the $1.2-million award on December 10 in Stockholm.

Scientists estimate that about 800 GPCRs mediate nearly every physiologic process in humans, from smell and taste to the fight-or-flight stress response to immune system function. At least 2 dozen GPCRs are thought to play roles in tumor growth, angiogenesis, or metastasis.

“Historically, it's always been the receptor tyrosine kinases that have been linked with cancer, but there's more and more evidence that GPCRs also play a central role,” says Jeffrey Benovic, PhD, chairman of the department of biochemistry and molecular biology at Thomas Jefferson University in Philadelphia, PA. “The field has really exploded over the past 5 to 10 years,” notes Benovic.

For much of the 20th century, scientists speculated that cells must have receptors to sense and respond to changes in their environment, but specifics of their structure and function remained a mystery. In an effort to identify receptors, Lefkowitz in 1968 began to attach radioisotopes to various hormones. Beginning with the β2-adrenergic receptor, his group ultimately identified 8 subtypes of adrenergic receptors.

A professor of biochemistry, immunology, and medicine at Duke University Medical Center in Durham, NC, Lefkowitz found the gene that codes for the β2-adrenergic receptor, work spearheaded in the mid-1980s by Kobilka. He and Kobilka discovered that the receptor consists of 7 hydrophobic spiral strings that snake through the cell membrane, giving it the same shape as the light receptor rhodopsin in the eye. Lefkowitz concluded that there must be a whole family of such receptors, which interact with G-proteins inside the cell.

Kobilka continued studying GPCRs after moving in 1989 to Stanford University's School of Medicine in Palo Alto, CA, where he is professor and chair of molecular and cellular physiology. In 2007, his team used crystallography to obtain the structure of an inactive β2-adrenergic receptor. Another breakthrough came in 2011, when it captured an image of an agonist-activated β2-adrenergic receptor transferring a signal to a G-protein.

Because about half of all drugs, including over-the-counter agents like antihistamines and aspirin, target GPCRs either directly or indirectly, researchers are incorporating the growing knowledge of GPCR biology and structure into drug design, says Jennifer Grandis, MD, a professor of otolaryngology and pharmacology at the University of Pittsburgh Medical School in Pennsylvania. For example, the chemokine receptor CXCR4 is overexpressed in at least 23 cancers. CXCR4 inhibitors are under study in patients with acute myeloid leukemia, lymphoma, and other cancers.

Additionally, researchers are studying combinations of agents that take aim at both GPCRs and other molecular targets. “We also need to identify those individuals who, based on their tumor's molecular profile, are most likely to respond to these therapeutic combinations,” says Grandis.

Brian Kobilka, MD, and colleagues determined the crystal structure of the activated β2-adrenergic receptor, a G-protein-coupled receptor, in complex with the heterotrimeric G-protein Gs, in 2011. The receptor is shown in magenta; the G-protein subunits are colored green, red, and blue.
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Brian Kobilka, MD, and colleagues determined the crystal structure of the activated β2-adrenergic receptor, a G-protein-coupled receptor, in complex with the heterotrimeric G-protein Gs, in 2011. The receptor is shown in magenta; the G-protein subunits are colored green, red, and blue.

Brian Kobilka, MD, and colleagues determined the crystal structure of the activated β2-adrenergic receptor, a G-protein-coupled receptor, in complex with the heterotrimeric G-protein Gs, in 2011. The receptor is shown in magenta; the G-protein subunits are colored green, red, and blue.
View largeDownload slide

Brian Kobilka, MD, and colleagues determined the crystal structure of the activated β2-adrenergic receptor, a G-protein-coupled receptor, in complex with the heterotrimeric G-protein Gs, in 2011. The receptor is shown in magenta; the G-protein subunits are colored green, red, and blue.

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Learning even more about GPCR structure is “one key to developing more effective cancer drugs,” says Benovic, who worked with Kobilka in the Lefkowitz lab in the 1980s. Many GPCRs, including CXCR4, normally activate signaling through both G-protein-dependent and arrestin-dependent pathways, but certain ligands can selectively trigger a particular pathway. These biased ligands, he says, may prove to be more effective drugs.

For more news on cancer research, visit Cancer Discovery online at http://CDnews.aacrjournals.org.

©2012 American Association for Cancer Research.
2012