Cancer Research UK scientists ‘bag up and bin’ weak spot in cancer cells
by Amy Swinderman  |  Email the author


LONDON— Researchers at Cancer Research UK have exposed a previously unrecognized cancer cell vulnerability that may provide a new therapeutic opportunity for the disease, according to a study recently published in Nature Cell Biology.
In the study, scientists at Cancer Research UK, a publicly funded charity dedicated to the prevention, diagnosis and treatment of cancer, removed a protein called FAK from mice and cancer cells grown in the lab. FAK is produced in much higher amounts in cancer cells and partners with another protein, SRC, and together, the two proteins cause tumors to grow and spread.  
The researchers found that removing—or blocking—FAK increases levels of un-partnered "free" SRC, which becomes toxic in high amounts. This should, in theory, trigger automatic cancer cell death—but the Cancer Research UK team discovered that cancer cells can get rid of the problematic SRC protein and still survive.  
By blocking FAK—and stopping cells that are disposing of SRC in the process—scientists may have a new, powerful route to destroy cancer cells, according to the study.  
"We've shown that cancer cells can adapt to the problems caused by stress, by hijacking normal cell waste disposal to 'bag up and bin' toxic proteins," says Prof. Margaret Frame, a Cancer Research UK scientist at the Edinburgh Cancer Research UK Centre. "This reveals a previously unknown weak spot in cancer cells— and a potential new pathway to tackle cancer. Combining drugs already in development, which block a protein called FAK, with techniques to stop cancer cells removing excess toxic SRC, would kill them."  
The study reports a mechanism for the regulation of active Src in cancer cells. Although "classical" autophagy can be induced via serum and nutrient starvation irrespective of FAK status, it is only in the absence of FAK, or disruption of integrin signaling through the FAK/Src pathway, that active Src is selectively targeted to autophagic puncta.  
Engagement of this autophagy pathway allows these cancer cells to "cope with" the stress of excessive, "untethered" Src activity and avoiding loss of viability. Importantly, equivalent FAK-proficient cancer cells are not similarly dependent on Src-selective autophagy for their survival, exposing a previously unrecognized cancer cell vulnerability, according to the researchers.
"This study has potential implications for the use of FAK inhibitors that are now undergoing clinical testing; it may be that simultaneous treatment with FAK and autophagy inhibitors could provide therapeutic benefit in some contexts," the researchers concluded. "The experiments we report in mouse pancreatic tissue demonstrate that autophagic targeting of active Src occurs in different tissue types and in vivo, implying that this is a common mechanism to cope with the stress of impaired flux through the integrin/Src/FAK pathway. It may also explain why FAK is commonly co-upregulated with Src in epithelial cancers, ensuring that flux through the pathway is appropriately maintained. "  
Cancer Research UK's network of more than 4,000 scientists, doctors and nurses support all research into all aspects of cancer.  
"Thanks to the generosity of the public's support we're able to invest in world-leading research such as this. By learning more about how cancer cells cheat death, we hope we'll discover new ways to prevent and treat the disease," said Dr. Julie Sharp, Cancer Research UK's senior science communications manager, in a statement. 

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