Overcoming resistance to a cancer drug
Drugs that target members of the EGFR family of proteins have proven effective for the treatment of certain types of cancer, including breast cancer. However, in a large number of patients for whom the treatment initially works well, the tumor recurs and is resistant to the effects of the drug. New insight into the mechanisms of tumor resistance to a drug known as gefitinib, which targets EGFR, has now been provided by a team of researchers at Vanderbilt University Medical Center, Nashville, and Massachusetts General Hospital Cancer Center, Charlestown. As discussed by both the authors and, in an accompanying commentary, Mark Greene and Qiang Wang, at the University of Pennsylvania Medical Center, Philadelphia, these observations help us understand why tumors become resistant to the effects of EGFR-targeted drugs, information that is essential if more effective therapies are to be developed.
The team, led by Carlos Arteaga and Jeffrey Engelman, generated cancer cells resistant to the effects of gefitinib and found that these cells were constantly sending signals from a protein on their surface known as IGF1R. This meant that two proteins known as IRS-1 and PI3K were always associated. If this association was disrupted then the cells once again became susceptible to the effects of gefitinib. Further analysis showed that if mice with a human tumor were treated with gefitinib and a drug inhibiting IGF1R their tumors did not recur, whereas neither drug alone could prevent tumor recurrence. The authors therefore suggest that drug combinations that target both EGFR and IGF1R might be of benefit to individuals with cancers that are responsive to EGFR-targeted therapies.
TITLE: Acquired resistance to EGFR tyrosine kinase inhibitors in cancer cells is mediated by loss of IGF-binding proteins
AUTHOR CONTACT:
Carlos L. Arteaga
Vanderbilt University Medical Center, Nashville, Tennessee, USA
Jeffrey A. Engelman
Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, Massachusetts, USA.
View the PDF of this article at: https://www.the-jci/article.php?id=34588
ACCOMPANYING COMMENTARY
TITLE: Mechanisms of resistance to ErbB-targeted cancer therapeutics
AUTHOR CONTACT:
Mark I. Greene
University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
View the PDF of this article at: https://www.the-jci/article.php?id=36260
How an anticancer drug dampens the immune system
Drugs known as HDAC inhibitors, which have antitumor activity and can be used to treat some forms of skin cancer and some types of leukemia, are also known to have anti-inflammatory properties, but the mechanisms by which they modulate the immune system have not been determined. New data, generated by Pavan Reddy and colleagues, at the University of Michigan Cancer Center, Ann Arbor, have now indicated one mechanism by which HDAC inhibitors modulate the mouse and human immune system and the information gained has been used to develop an approach to protect mice from graft-versus-host disease after bone marrow transplantation.
In the study, two different HDAC inhibitors were shown to prevent mouse and human immune cells known as dendritic cells (DCs) from initiating proinflammatory immune responses in vitro. Further, if DCs treated ex vivo with HDAC inhibitors were injected into mice after they had received a bone marrow transplant, the incidence and severity of graft-versus-host disease was dramatically reduced. Detailed analysis revealed that the HDAC inhibitors mediated their effects by inducing DCs to express more of a molecule known as IDO, which is a suppressor of DC function. The authors therefore hope that their data provide support for studies to determine whether HDAC inhibitors might be of benefit to individuals receiving bone marrow transplants and to those with other immune-mediated diseases.
TITLE: Histone deacetylase inhibition modulates indoleamine 2,3-dioxygenase-dependent DC functions and regulates experimental graft-versus-host disease in mice
AUTHOR CONTACT:
Pavan Reddy
University of Michigan Cancer Center, Ann Arbor, Michigan, USA.
View the PDF of this article at: https://www.the-jci/article.php?id=34712
A prickly problem: hedgehog signaling in the blood vessels of the heart
New data, generated by David Ornitz and colleagues, at Washington University School of Medicine, St. Louis, have indicated a crucial role for signaling pathways that involve the protein sonic hedgehog in maintaining the blood vessels that supply the mouse heart and keep it beating. These data have implications for drug development as they suggest that antagonists of hedgehog signaling pathways, such as those being developed as anticancer therapeutics, might have unwanted side effects.
In the study, mice lacking the ability to mediate hedgehog signaling in cells that form part of the blood vessels that supply the heart were found to die of heart failure. This was because in the absence of hedgehog signaling the blood vessels of the heart were lost, meaning that the heart cells were no longer supplied with enough oxygen and died. Although these data indicate a need for caution when developing clinical antagonists of hedgehog signaling, it is possible that the degree of inhibition needed to have a clinical effect on tumor development might not have the effect on blood vessels of the heart that completely eliminating expression of the protein does.
TITLE: Hedgehog signaling is critical for maintenance of the adult coronary vasculature in mice
AUTHOR CONTACT:
David M. Ornitz
Washington University School of Medicine, St. Louis, Missouri, USA.
View the PDF of this article at: https://www.the-jci/article.php?id=34561
Immune cells cause inflammation by destroying an anti-inflammatory protein
Among the first cells of the immune system to respond to microorganisms that invade our body are neutrophils. Although neutrophils are considered the "good guys" in such circumstances, they also contribute to the noninfectious chronic inflammation that underlies various diseases, including autoimmune diseases such as rheumatoid arthritis. One mechanism by which neutrophils protect us is to internalize microorganisms and destroy them using proteins known as neutrophil serine proteases (NSPs), but whether NSPs have a role in noninfectious chronic inflammation has not been clearly determined. However, using mice lacking two very similar NSPs, PR3 and NE, a team of researchers at the Max-Planck-Institute of Neurobiology, Germany, have now shown that these two NSPs have a crucial role in one form of noninfectious chronic inflammation. Detailed analysis revealed that PR3 and NE destroy an anti-inflammatory molecule known as PGRN and in this way help to promote inflammation in the absence of invading microorganisms. The authors therefore suggest that these data provide rationale for considering inhibitors of NSPs as anti-inflammatory drugs.
TITLE: Proteinase 3 and neutrophil elastase enhance inflammation in mice by inactivating antiinflammatory progranulin
AUTHOR CONTACT:
Kai Kessenbrock
Max-Planck-Institute of Neurobiology, Martinsried, Germany.
Dieter E. Jenne
Max-Planck-Institute of Neurobiology, Martinsried, Germany.
View the PDF of this article at: https://www.the-jci/article.php?id=34694
Source: Karen Honey
Journal of Clinical Investigation
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