All tyrosine kinase inhibitor-resistant chronic myelogenous cells are highly sensitive to Ponatinib
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Ophélie CASSUTO1-4*, Maeva DUFIES1-2*, Arnaud JACQUEL1-2, Guillaume ROBERT1-2, Clémence GINET1-2, Alix DUBOIS1-2, Amine HAMOUDA1-2, Alexandre PUISSANT1,2,#, Fredéric LUCIANO1-2, Jean-Michel KARSENTI3, Laurence LEGROS3, Jill Patrice CASSUTO3, Pascal LENAIN4, Patrick AUBERGER1-3
1 C3M/ INSERM U1065 Team Cell Death, Differentiation, Inflammation and Cancer, Nice, France
2 Equipe Labellisée Ligue Nationale contre le Cancer 2011-2013, Paris, France
3 Service d’Hématologie Clinique et de Transplantation, CHU de Nice, France
4 Centre Henri Becquerel, CLCC, Rouen, France
# Dana-Farber Cancer Institute, Pediatric-Oncology department, 450 Brookline Avenue, Boston, MA, USA
* denotes equal contribution
Patrick Auberger, email:
Keywords: CML, BCR ABL, TKI, Resistance, Ponatinib
Received: October 02, 2012, Accepted: November 12, 2012, Published: November 14, 2012
The advent of tyrosine kinase inhibitor (TKI) therapy has considerably improved the survival of patients suffering chronic myelogenous leukemia (CML). Indeed, inhibition of BCR-ABL by imatinib, dasatinib or nilotinib triggers durable responses in most patients suffering from this disease. Moreover, resistance to imatinib due to kinase domain mutations can be generally circumvented using dasatinib or nilotinib, but the multi-resistant T315I mutation that is insensitive to these TKIs, remains to date a major clinical problem. In this line, ponatinib (AP24534) has emerged as a promising therapeutic option in patients with all kinds of BCR-ABL mutations, especially the T315I one. However and surprisingly, the effect of ponatinib has not been extensively studied on imatinib-resistant CML cell lines. Therefore, in the present study, we used several CML cell lines with different mechanisms of resistance to TKI to evaluate the effect of ponatinib on cell viability, apoptosis and signaling. Our results show that ponatinib is highly effective on both sensitive and resistant CML cell lines, whatever the mode of resistance and also on BaF3 murine B cells carrying native BCR-ABL or T315I mutation. We conclude that ponatinib could be effectively used for all types of TKI-resistant patients.
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