All tyrosine kinase inhibitor-resistant chronic myelogenous cells are highly sensitive to Ponatinib

Abstract

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.

A molecular and biophysical comparison of macromolecular changes in imatinib-sensitive and imatinib-resistant K562 cells exposed to ponatinib

“…6). Previously, apoptotic effects of ponatinib were reported in several types of resistant CML cell lines [35], but in this study, we also showed the effects of ponatinib on cell cycle and macromolecular changes in both K562 and K562/IMA-3 cells. Moreover, FTIR results showed that the band around the 3300 cm −1 band (amide A) is considered to be due to proteins and polysaccharides.…”

Ponatinib circumvents all types of imatinib resistance in chronic myelogenous leukemia cell lines

“…5 In a recent phase I study including 81 patients, among which 60 with CML and five with Ph-positive ALL, ponatinib was shown to be highly active in heavily pretreated patients (treatments were involving up to three TKIs) with Ph-positive leukemia (essentially CML) with resistance to TKIs, including patients with the T315I mutation, other mutations or no mutations. 7 Globally, these results suggest that, in addition to T315I patients, ponatinib could be widely used in CMLresistant patients, whatever the supposed mode of resistance to first-line TKIs, an observation that is in agreement with our own in vitro observations 6 (Fig. 1).…”

Sensitivity of imatinib-resistant T315I BCR-ABL CML to a synergistic combination of ponatinib and forskolin treatment

“…In vitro studies have revealed that IC 50 levels of ponatinib require doses of approximately 8 nM, while most drug-resistant CML cell lines require 30 nM ponatinib to be effective [9]. The data presented in this study suggest that ponatinib IC 50 values can be reduced to 0.5 nM when used in combination with forskolin at a concentration of 20 uM.…”

“…Phase I clinical trials of ponatinib in refractory Ph chromosome-positive leukemias demonstrated high efficacy against multiple resistant forms including those harboring the T315I mutation [8]. Ponatinib has also been demonstrated to be effective against the T315I TKI-resistant CML cells; however, serious adverse side effects such as blood clots and narrowing of blood vessels were reported [9–11]. Patients receiving TKI therapy are at increased risk of developing hypertension, arterial/venous thromboembolic events, cerebral ischemia, or myocardial infarction due to secondary off-target effects of TKIs.…”