UCSF oncologist Mark Moasser, MD, works with Natalia Sergina, PhD, now a former postdoctoral fellow in his lab, where research has led to a new strategy for treating a common form of breast cancer.
Sorting out the HER2 signaling pathwayThe idea for using higher dosages emerged from lab findings. A compensatory biochemical response permits HER2-driven tumor cells to survive all but complete inhibition of HER2, a team led by Moasser and UCSF colleague Kevan Shokat, PhD, reported in a 2007 study. HER2 signals must be relayed through other proteins downstream along the biochemical signaling pathway. The downstream signaling network creates a buffer, so that signaling can withstand drug treatment, Moasser says. If the dosage is increased, signaling revs up to compensate -- up to a point. Dosages that are higher still can stop signaling, but are toxic when given continually. A minimum of three days without HER2 signaling is needed to kill HER2-positive breast cancer cells, Moasser says. HER2 is able to transmit signals despite treatment thanks to its partner HER3. This is because HER3 is connected to a complex network that functions like an amplifier volume knob. If signaling decreases due to drug therapy, the network can increase signaling volume to compensate. Understanding the network is a principle challenge for Moasser. “There’s a complex network in which HER2 and HER3 operate,” Moasser says. “We want to reduce its complexity. We want to know how big it is. We want to know where it is susceptible to attack.” Some of the most important proteins in HER2’s signaling pathway are downstream from HER3, Moasser says. He says resistance to current treatments for HER2-driven breast cancer might one day be overcome by combining current HER2 inhibitors with other targeted drugs that separately attack either HER3 or proteins downstream in the signaling pathway. In collaboration with Joe Gray, PhD, head of UCSF’s Breast Oncology Program and director of the Life Sciences Division at Lawrence Berkeley National Laboratory, Moasser is taking a systems biology approach. The researchers are trying to unravel the complexities of the network and to model it with mathematical formulas. These models would then allow computational methods to predict how cells will respond to specific drug treatments. Moasser also continues to work with Shokat, a chemist who is innovative at making inhibitors that specifically target individual proteins. “Step by step we march down the pathway and interrogate the signaling circuitry with these inhibitors,” Moasser says. “At every step we measure how the cell responds.” Although complexities of HER2-driven breast cancers have not yet been completely elucidated, these tumors may be less complex and resilient than many other cancers, Moasser says. “In most solid tumors there are many signaling pathways that go wrong, and many genes that are mutated,” he says. “I think that this cancer is more simplistic, and that HER2 is the critical driver. I think we should be able to cure this cancer if we can shut down HER2, even in advanced cases.” There is a precedent for using targeted drugs to vanquish cancers driven primarily by a single signaling pathway in the treatment of non-Hodgkin’s lymphoma and chronic myelogenous leukemia.
Resiliency and Vulnerability in the HER2-HER3 Tumorigenic Driver
Dhara N. Amin, Natalia Sergina, Deepika Ahuja, Martin McMahon, Jimmy A. Blair, Donghui Wang, Byron Hann, Kevin M. Koch, Kevan M. Shokat and Mark M. Moasser
Science Translational Medicine (January 27, 2010)Summary
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