Premium
Ponatinib may overcome resistance of FLT 3‐ ITD harbouring additional point mutations, notably the previously refractory F 691I mutation
Author(s) -
Zirm Elisabeth,
SpiesWeisshart Bärbel,
Heidel Florian,
Schnetzke Ulf,
Böhmer FrankDietmar,
Hochhaus Andreas,
Fischer Thomas,
Scholl Sebastian
Publication year - 2012
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/j.1365-2141.2012.09085.x
Subject(s) - ponatinib , mutation , tyrosine kinase , point mutation , cancer research , biology , medicine , dasatinib , genetics , signal transduction , gene
Summary Fms ‐like tyrosine kinase ( FLT 3) mutations are the most frequent mutations in patients with acute myeloid leukaemia ( AML ) that confer a poor prognosis. Constitutively active FLT 3‐ ITD (internal tandem duplications) mutations define a promising target for therapeutic approaches using small molecule inhibitors. However, several point mutations of the FLT 3 tyrosine kinase domain ( FLT 3‐ TKD ) have been identified to mediate resistance towards FLT 3 tyrosine kinase inhibitors ( FLT 3‐ TKI ), including secondary mutations of FLT 3 . We investigated the cellular effects of the recently characterised FLT 3‐ TKI ponatinib ( AP 24534) on murine myeloid cells transfected with FLT 3‐ ITD with or without additional point mutations of the FLT 3‐ TKD including the (so far) multi‐resistant F691I mutation. Ponatinib effectively induced apoptosis not only in the parental FLT 3‐ ITD cell line but also in all stably transfected subclones harbouring additional FLT 3‐ TKD point mutations (N676D, F691I or G697R). These observations correlated with a strong inhibition of FLT 3‐ ITD and its downstream targets STAT 5, AKT and ERK 1/2 upon ponatinib incubation, as determined by Western blotting. We conclude that ponatinib represents a promising FLT 3‐ TKI that should be further investigated in clinical trials. The targeted therapy of FLT 3‐ ITD ‐positive AML with ponatinib might be associated with a lower frequency of secondary resistance caused by acquired FLT 3‐ TKD mutations.