Navigation Links
A hijacking of healthy cellular circuits
Date:4/8/2013

April 8, 2013, New York, NY and San Diego Calif. Proteins that control cell growth are often mutated in cancer, and their aberrant signaling drives the wild proliferation of cells that gives rise to tumors. One such protein, the epidermal growth factor receptor (EGFR), fuels a wide variety of cancersincluding a highly malignant brain cancer known as glioblastoma. Yet drugs devised to block its signaling tend to work only for a short while, until the cancer cells adapt to evade the therapy. So far, much of the research examining such drug resistance has focused on how mutations of other proteins in cancer cells allow them to resist drugs.

But not all drug-resistant tumors harbor those additional mutations, suggesting that they have evolved alternative resistance mechanisms. In the current issue of Cancer Discovery, a team led by Paul Mischel at the Ludwig Institute for Cancer Research and Steven Bensinger at the University of California, Los Angeles, identifies a unique mechanism by which glioblastoma cells develop resistance to drugs that target EGFR signaling. The cells accomplish this feat not through mutation, but by hijacking the signaling of a perfectly normal cell surface receptor named platelet-derived growth factor receptor-β (PDGFRβ). Targeting both receptors at once, the researchers report, prevents resistance and suppresses glioblastoma tumors in laboratory models.

"Our findings highlight the remarkable adaptability of cancer cells and how they harness multiple mechanisms to maintain the growth signals critical to their survival. These results could have implications for our understanding of a wide variety of cancers," says Mischel, MD, member of the Ludwig Institute at the University of California San Diego.

Mischel, Bensinger and their colleagues began their study by exploring how blocking EGFR alters signaling in glioblastoma cells. To do so, they transplanted into mice glioblastoma tumors that are naturally fueled by a permanently activated mutant of EGFR. They then treated the mice with a drug named erlotinib, which inhibits EGFR.

What they saw was that one receptor in particularPDGFRβwas highly expressed and active in all treated tumor cells, but virtually absent in tumors that were spared treatment. The researchers detected the same pattern in cultures of cells derived from a variety of glioblastoma tumors. This suggested that cancer cells in which EGFR signaling is blocked respond by expressing PDGFRβ to compensate for the loss of that critical signal.

To determine whether the phenomenon occurred in patients as well, the team examined tumor samples collected in a clinical trial of another EGFR-targeting drug named lapatinib. "Across tumors," says Mischel, "we saw a reciprocal relationship between the activation of PDGFRβ and the mutant form of the EGFR. This established that what we were seeing in lab experiments was happening in people actually undergoing treatment with EGFR targeting drugs."

Using pharmacologic and genetic techniques to tease apart the signaling pathways responsible for this effect, the researchers found that two distinct biochemical circuits switched on by EGFR suppressed the expression of the PDGFRβ gene. One is mediated by a protein named mTORC1, and another by a protein named MEK. "When one blocks EGFR signaling with a drug," explains Mischel, "that repression is lifted. But, more importantly, these tumors do not need PDGFRβ signaling to survive until you block EGFR." At that point, the tumors become highly dependent on PDGFRβ.

"It's almost like a game of whack-a-mole," says Mischel. "You use a drug to suppress a choice target, and something else pops up to take its place and keep the cells alivein this case a growth factor receptor that is perfectly normal in physiological terms." Notably, such resistance mechanisms, unlike genetic mutation, are very difficult to anticipate.

When they are, however, they can illuminate novel therapeutic strategies. Mischel and Bensinger's team found, for example, that both glioblastoma cell cultures derived from patients and tumors transplanted into mice were potently suppressed when both receptors were blocked at once. "This suggests that if you target both receptors," says Mischel, "you might be able to prevent drug resistance."

Though the study led by Mischel and Bensinger focuses on glioblastoma, its findings are relevant to many other cancersand not just because aberrant EGFR signaling drives the growth of many types of tumors.

The next step, Mischel says, is to test in clinical trials how targeting both receptors affects the treatment of glioblastoma. He and his colleagues also hope to work with other Ludwig researchers to explore small molecule inhibitors of PDGFRβ and to examine whether similar drug resistance mechanisms are found in other cancers as well.


'/>"/>

Contact: Rachel Steinhardt
rsteinhardt@licr.org
212-450-1582
Ludwig Institute for Cancer Research
Source:Eurekalert

Related biology news :

1. Horticultural hijacking
2. To drive infections, a hijacking virus mimics a cells signaling system
3. Unhealthy eating can make a bad mood worse
4. Stronger support needed for healthy beverage practices in child care
5. Neuronal activity induces tau release from healthy neurons
6. Building healthy bones takes guts
7. Healthy seeds -- treated environmentally friendly
8. Poor mental health leads to unhealthy behaviors among low-income adults
9. Foods identified as whole grain not always healthy
10. UC Davis study deflates notion that pear-shaped bodies more healthy than apples
11. R U eating healthy 2day?
Post Your Comments:
*Name:
*Comment:
*Email:
(Date:4/19/2016)... , UAE, April 20, 2016 ... be implemented as a compact web-based "all-in-one" system solution ... the biometric fingerprint reader or the door interface with ... of modern access control systems. The minimal dimensions of ... ID readers into the building installations offer considerable freedom ...
(Date:3/31/2016)... 2016   LegacyXChange, ... "Company") LegacyXChange is excited to release its ... to be launched online site for trading 100% guaranteed ... will also provide potential shareholders a sense of the ... an industry that is notorious for fraud. The video ...
(Date:3/22/2016)... PROVO and SANDY, Utah ... (NSO), which operates the highest sample volume laboratory in ... Tute Genomics and UNIConnect, leaders in clinical sequencing informatics ... the launch of a project to establish the informatics ... NSO has been contracted by the ...
Breaking Biology News(10 mins):
(Date:4/28/2016)... Conn. (PRWEB) , ... April 28, 2016 , ... ... financing and ongoing support for Connecticut's innovative, growing companies, today announced the launch ... health and financial technology (fintech) companies. , “VentureClash looks to attract ...
(Date:4/27/2016)... ... 2016 , ... Shimadzu Scientific Instruments (SSI) will be showcasing ... Conference and Expo. Shimadzu’s high-performance instruments enable laboratories to test cannabis products for ... stop by booth 1021 to learn how Shimadzu’s instruments can help improve QA/QC ...
(Date:4/27/2016)... ... April 27, 2016 , ... The Board ... the appointment of John Tilton as Chief Commercial Officer.  Mr. Tilton joined Biohaven ... the founding commercial leaders responsible for the commercialization of multiple orphan drug indications. ...
(Date:4/27/2016)... ... ... Global Stem Cells Group and the University of Santiago Biotechnology Lab have ... for potential stem cell protocol management for 2016 – 2020. , In 2015, ... establish a working agenda and foster initiatives to promote stem cell research and development ...
Breaking Biology Technology: