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.

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.

Wesam Ahmed and Richard A. Van Etten

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

Ghalaut VS1, Sangwan L, Dahiya K, Ghalaut PS, Dhankhar R, Saharan R.

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.

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

Josu de la Fuente,1 Andre Baruchel,2 Andrea Biondi,3 Eveline de Bont,4 Marie-Francoise Dresse,5 Meinolf Suttorp6 and
Frederic Millot7 on behalf of the International BFM Group (iBFM) Study Group Chronic Myeloid Leukaemia Committee

Paediatrics Department, Saint Mary Hospital, London, UK, 2Department of Paediatric Haematology, Hopital Robert Debre, Paris,
France, 3 M. Tettamanti Research Centre, Paediatrics Department, University of Milano-Bicocca, Monza, Italy, 4 Department of Paediatric Oncology, Beatrix Children’s Hospital, Groningen, the Netherlands, 5 Department of Paediatric Haematology-Oncology, CHR La Citadelle, Liege, Belgium, 6