10 Mar 2014
Researchers in Manchester have investigated the stickiness of leukaemia cells, and whether this is linked to drug resistance.
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10 Mar 2014
News | September 03, 2014 | Leukemia & Lymphoma, Chronic Myeloid Leukemia, Hematologic Malignancies
By Dave Levitan
STAT3 inhibition using a novel compound restored sensitivity to tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML) cells that had shown resistance independent of BCR-ABL1 kinase activity, according to a new study published in the journal Leukemia. The findings could help fill gaps in CML treatment for patients with unexplained resistance to TKIs.
Sustained inhibition of STAT5, but not JAK2, is essential for TKI-induced cell death in chronic myeloid leukemia
L Schafranek1,2,3, E Nievergall1,2,3, J A Powell4,5, D K Hiwase3,6, T Leclercq1,3, T P Hughes1,2,3,6,7 and D L White1,2,3,4
Kinase inhibitors block proliferative signals in BCR-ABL1+ leukemic cells, but their capacity to induce apoptosis is poorly understood. Initial studies suggested that very brief exposure to kinase inhibitors was sufficient to induce apoptosis in chronic myeloid leukemia (CML) cells. However, flaws in this experimental model have subsequently been identified, leading to the conclusion that apoptosis only occurs with sustained low-level kinase inhibition. Thus, the minimum duration of complete kinase inhibition required to commit CML cells to death is unknown. Here we confirm that <1 h is insufficient to induce significant commitment to death in BCR-ABL1+ cell lines and in primary CD34+ progenitor cells, and establish that commitment to cell death only occurs if kinase inhibition is maintained for 4 h or more. Remarkably, signal transducer and activator of transcription 5 (STAT5) inhibition in combination with transient (<1 h) tyrosine kinase inhibitor (TKI) exposure proved lethal for CML progenitors, despite the reactivation of Bcr-Abl after 1 h. JAK kinase inhibition did not induce cell death in combination with transient TKI exposure. Thus, STAT5 appears to be a critical determinant of the time-dependent sensitivity of CML progenitor cells to TKI treatment in a Bcr-Abl-dependent, but JAK-independent, manner. We conclude that combining kinase inhibition with STAT5 inhibition represents a promising therapeutic approach in BCR-ABL1+ leukemias.
Alternative approaches to eradicating the malignant clone in chronic myeloid leukemia: tyrosine-kinase inhibitor combinations and beyond
Wesam Ahmed and Richard A. Van Etten
Safety of bosutinib versus imatinib in the phase 3 BELA trial in newly diagnosed chronic phase chronic myeloid leukemia
Carlo Gambacorti-Passerini1,*, Jorge E. Cortes2, Jeff H. Lipton3, Anna Dmoszynska4, Raymond S. Wong5, Victor Rossiev6, Dmitri Pavlov7, Karin Gogat Marchant8, Ladan Duvillié8, Navin Khattry9, Hagop M. Kantarjian2 andTim H. Brümmendorf10,11
Megan Brooks July 25, 2014
With the rapid and widespread uptake of tyrosine kinase inhibitors (TKIs) in oncology over the past several years, serious drug–drug interactions are an "increasing risk," according a new report.
Amina Haouala1, Nicolas Widmer1, Michel A. Duchosal2, Michael Montemurro3, Thierry Buclin1, and Laurent A. Decosterd1
Effect of imatinib therapy with and without turmeric powder on nitric oxide levels in chronic myeloid leukemia
Ghalaut VS1, Sangwan L, Dahiya K, Ghalaut PS, Dhankhar R, Saharan R.
MDR1 expression predicts outcome of Ph+ chronic phase CML patients on second-line nilotinib therapy after imatinib failure
M Agrawal1, B Hanfstein1, P Erben1, D Wolf2, T Ernst3, A Fabarius1, S Saussele1, D Purkayastha4, R C Woodman4, W-K Hofmann1, R Hehlmann1, A Hochhaus3 and M C Müller1
Nilotinib was able to impede proliferation of MDR1-overexpressing imatinib-resistant cells. High MDR1 gene expression might identify patients whose mode of imatinib resistance is essentially determined by increased efflux activity of MDR1 and therefore can be overcome by second-line nilotinib treatment.
Deep molecular responses achieved in patients with CML-CP who are switched to nilotinib after long-term imatinib
Timothy P. Hughes1,*, Jeffrey H. Lipton2, Nelson Spector3, Francisco Cervantes4, Ricardo Pasquini5, Nelma Cristina D. Clementino6, Pedro Enrique Dorlhiac Llacer7, Anthony P. Schwarer8, Francois-Xavier Mahon9, Delphine Rea10, Susan Branford11, Das Purkayastha12, LaTonya Collins12, Tomasz Szczudlo12, and Brian Leber13