The genetic basis of sensitivity to Abl kinase inhibitors in Ph+ALL

Coordinator:    Prof. Dr. Justus Duyster
Institution: III. Medizinische Klinik, Klinikum rechts der Isar der TU München
The Bcr-Abl protein gives rise to a specific form of blood cancer called chronic myelogenous leukemia (CML). Bcr-Abl functions as a kinase, which activates cellular signaling cascades. Imatinib (Glivec) was approved for the treatment of CML in 2001. Imatinib binds to Bcr-Abl, thereby inhibiting its kinase activity. Many CML patients treated with imatinib experience durable remissions. However in a proportion of cases, clinical resistance to imatinib emerges. We and others have shown that different mutations in the BCR-ABL gene can cause clinical resistance to imatinib. These mutations give rise to structural changes of the imatinib-binding site which impede binding of the drug: imatinib loses its activity. "Second generation" Bcr-Abl inhibitors can overcome imatinib resistance. However, resistance mutations can emerge with 2nd generation inhibitors as well. We have developed a cell culture-based strategy that allows to predict specific profiles of resistance mutations for different inhibitors, making it possible to determine combinations of drugs with overlapping resistance profiles and to design sequential treatment strategies. Using this strategy, we were able to show that BCR-ABL mutations that came up with imatinib exactly match those energing in imatinib treated CML patients. In contrast, second generation inhibitors give rise to resistant cell clones at a lower frequency, and to distinct resistance profiles. For example, we determined the resistance profile for the 2nd generation inhibitor nilotinib, which later on was confirmed in clinical trials. This strategy can also be used to study inhibitor resistance in other forms of cancer. However, in about half of the cases, neither resistant cell lines nor resistant leukemia cells in patients do carry mutations in the target kinase. We are currently focussing on the molecular mechanisms underlying this "wild-type" resistance, in order to identify novel targets for therapeutic intervention. These findings might anticipate results of long-winded clinical trials and thereby might contribute in the development of personalized medicine, with the ultimate goal to increase remission rates and to prolong life in patients suffering from CML and other forms of cancer.

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