TITLE

The sonic hedgehog factor GLI1 imparts drug resistance through inducible glucuronidation

AUTHOR(S)
Zahreddine, Hiba Ahmad; Culjkovic-Kraljacic, Biljana; Assouline, Sarit; Gendron, Patrick; Romeo, Andrea A.; Morris, Stephen J.; Cormack, Gregory; Jaquith, James B.; Cerchietti, Leandro; Cocolakis, Eftihia; Amri, Abdellatif; Bergeron, Julie; Leber, Brian; Becker, Michael W.; Pei, Shanshan; Jordan, Craig T.; Miller, Wilson H.; Borden, Katherine L. B.
PUB. DATE
July 2014
SOURCE
Nature;7/3/2014, Vol. 511 Issue 7507, p90
SOURCE TYPE
Academic Journal
DOC. TYPE
Article
ABSTRACT
Drug resistance is a major hurdle in oncology. Responses of acute myeloid leukaemia (AML) patients to cytarabine (Ara-C)-based therapies are often short lived with a median overall survival of months. Therapies are under development to improve outcomes and include targeting the eukaryotic translation initiation factor (eIF4E) with its inhibitor ribavirin. In a Phase II clinical trial in poor prognosis AML, ribavirin monotherapy yielded promising responses including remissions; however, all patients relapsed. Here we identify a novel form of drug resistance to ribavirin and Ara-C. We observe that the sonic hedgehog transcription factor glioma-associated protein 1 (GLI1) and the UDP glucuronosyltransferase (UGT1A) family of enzymes are elevated in resistant cells. UGT1As add glucuronic acid to many drugs, modifying their activity in diverse tissues. GLI1 alone is sufficient to drive UGT1A-dependent glucuronidation of ribavirin and Ara-C, and thus drug resistance. Resistance is overcome by genetic or pharmacological inhibition of GLI1, revealing a potential strategy to overcome drug resistance in some patients.
ACCESSION #
96923490

 

Related Articles

  • Comparison of consolidation strategies in acute myeloid leukemia: high-dose cytarabine alone versus intermediate-dose cytarabine combined with anthracyclines. Kim, Dae; Kang, Ka-Won; Lee, Se; Park, Yong; Sung, Hwa; Kim, Seok; Choi, Chul; Kim, Byung // Annals of Hematology;Sep2015, Vol. 94 Issue 9, p1485 

    We compared the efficacy of high-dose cytarabine alone to that of intermediate-dose cytarabine combined with anthracyclines as consolidation therapy. Patients enrolled in the Korea University acute myeloid leukemia (AML) registry received remission induction chemotherapy with the same standard...

  • Barasertib improved survival in AML.  // Hem/Onc Today;6/10/2013, Vol. 14 Issue 11, p9 

    The article focuses on the effectiveness of Barasertib in fighting acute myeloid leukemia, which was able to deliver improved survival and manageable toxicity compared to low-dose cytosine arabinoside when used in affected older patients.

  • Hemophagocytic syndrome in children with acute monoblastic leukemia—another cause of fever of unknown origin. Lackner, H.; Seidel, M. G.; Strenger, V.; Sovinz, P.; Schwinger, W.; Benesch, M.; Sperl, D.; Urban, C. // Supportive Care in Cancer;Dec2013, Vol. 21 Issue 12, p3519 

    Purpose: Intensification of antileukemic treatment and progress in supportive management have improved the survival rates of children with acute myeloid leukemia (AML). However, morbidity and early mortality in these patients are still very high, especially in children with acute monoblastic...

  • POST-REMISSION THERAPY OF ADULT ACUTE MYELOID LEUKEMIA: HIGH DOSE CYTOSINE-ARABINOSIDE VERSUS OTHER CONSOLIDATION REGIMENS. ZEREMSKI, Vanja; SAVIĆ, Aleksandar // Medicinski Pregled / Medical Review;Mar/Apr2014, Vol. 67 Issue 3/4, p83 

    Introduction. Modern therapy makes it possible for 60-80% patients with acute myeloid leukemia to achieve complete remission after induction therapy. However, most of them will relapse within six months to a year without additional cytostatic therapy. The questions regarding post-remission...

  • Update on Epidemiology of and Preventive Strategies for Invasive Fungal Infections in Cancer Patients. Perfect, John R.; Hachem, Ray; Wingard, John R. // Clinical Infectious Diseases;Nov2014 Supplement, Vol. 59 Issue suppl_5, pS352 

    Changes in antineoplastic treatments and transplant practices are driving shifts in the epidemiology of invasive fungal diseases (IFDs). Patients with acute myelogenous leukemia (AML) and those undergoing bone marrow transplant (BMT) are at greatest risk for contracting IFDs. Unfortunately,...

  • Differentiation therapy in acute myelogenous leukemia (non-APL). Waxman, S // Leukemia (08876924);Mar2000, Vol. 14 Issue 3, p491 

    Successful treatment of acute promyelocytic leukemia (APL) has identified several novel approaches to induce leukemic cell differentiation and selective apoptosis by overcoming the site-specific transcriptional repression by dominant fusion leukemogenic proteins characteristic of APL and other...

  • Treatment of relapsed and refractory acute myelogenous leukemia. Estey, E H // Leukemia (08876924);Mar2000, Vol. 14 Issue 3, p476 

    Evidence suggests that the salvage therapy utilized for relapsed and refractory acute myelogenous leukemia (AML) should differ based on the duration of a patient's complete remission (CR), the principal predictor of outcome. While standard regimens have produced higher CR rates than...

  • Gemtuzumab ozogamicin: A Viewpoint by Michael L. Grossbard. Grossbard, M.L. // Drugs;Jul2001, Vol. 61 Issue 9, p1323 

    Focuses on gemtuzumab ozogamicin therapy for acute myelocytic leukemia. Classification of gemtuzumab ozogamicin; Side effects of the therapy.

  • Gemtuzumab ozogamicin: A Viewpoint by Frederick R. Appelbaum. Appelbaum, F.R. // Drugs;Jul2001, Vol. 61 Issue 9, p1323 

    Weighs the efficacy of gemtuzumab ozogamicin as treatment for acute myeloid leukemia. Advantages of gemtuzumab ozogamicin over standard chemotherapy; Information on studies regarding its inclusion to combination therapy.

Share

Read the Article

Courtesy of THE LIBRARY OF VIRGINIA

Sorry, but this item is not currently available from your library.

Try another library?
Sign out of this library

Other Topics