Simultaneous targeting of Aurora kinases and Bcr-Abl kinase by the small molecule inhibitor PHA-739358 is effective against imatinib-resistant BCR-ABL mutations including T315I

Abstract

The emergence of resistance to imatinib (IM) mediated by mutations in the BCR-ABL domain has become a major challenge in the treatment of chronic myeloid leukemia (CML). Here, we report on studies performed with a novel small molecule inhibitor, PHA-739358, which selectively targets Bcr-Abl and Aurora kinases A to C. PHA-739358 exhibits strong antiproliferative and proapoptotic activity against a broad panel of human BCR-ABL-positive and -negative cell lines and against murine BaF3 cells ectopically ex-

Seeking the causes and solutions to imatinib-resistance in chronic myeloid leukemia

“…138 It has also demonstrated in-vitro activity against both wild-type Bcr-Abl and cells possessing the T315I mutation. 139 Preclinical data also suggested activity against CD34 þ CML progenitor cells from previously untreated patients, as well as from those derived from imatinib-resistant KW-2449 (Kyowa Hakko Kirin Pharma, Tokyo, Japan) KW-2449 is also an orally bioavailable Aurora kinase A and B inhibitor with concurrent nanomolar range activity against Abl, including the T315I, Flt3 and FGFR1. 143,144 In a phase I study, KW-2449 was administered between 25-500 mg/day utilizing a twice-daily dosing scheme for 14-days with a 7-28 days rest period.…”

Aurora kinase inhibitors: novel small molecules with promising activity in acute myeloid and Philadelphia-positive leukemias

“…Aurora kinase inhibitors such as MK-0457, danusertib and AT9283, with efficacy in Ph þ leukemia, clearly inhibit both Aurora and ABL signalling, whereas imatinib does not inhibit phosphorylation of the classic Aurora B downstream mechanistic biomarker, histone H3. 22,28,31 In TKI-resistant cells, including T315I mutants, ABL signalling is inhibited by Aurora kinase inhibitors but not by imatinib or dasatinib. 28,31 Preclinical studies of danusertib have also demonstrated dosedependent inhibition of BCR-ABL, with BCR-ABL inhibition occurring at lower concentrations than those required for Aurora inhibition.…”

“…22,28,31 In TKI-resistant cells, including T315I mutants, ABL signalling is inhibited by Aurora kinase inhibitors but not by imatinib or dasatinib. 28,31 Preclinical studies of danusertib have also demonstrated dosedependent inhibition of BCR-ABL, with BCR-ABL inhibition occurring at lower concentrations than those required for Aurora inhibition. 32 Finally, murine BaF3 cells have been shown to be less sensitive to MK-0457 than BaF3 cells ectopically expressing either wild-type or mutant BCR-ABL.…”

“…34 It should also be noted that preclinical studies have demonstrated synergistic cytotoxicity for danusertib with imatinib and for MLN8237 with the TKI nilotinib. 31,35 Although synergistic, whether the enhanced cytotoxicity is primarily due to increased BCR-ABL inhibition or the additional Aurora kinase Aurora kinase inhibitors in leukemia AS Moore et al Table 2 Aurora, FLT3 and ABL kinase profiles of Aurora, FLT3 and tyrosine kinase inhibitors inhibition remains unclear. Combination therapy of this type has the potential to reduce the emergence of imatinib-resistant cell lines, but more clinical experience with Aurora kinase inhibitors in large trials of TKI-resistant disease will need to be established before combination trials can be considered.…”

Extending the duration of response in chronic myelogenous leukemia: targeted therapy with sequential tyrosine kinase inhibitors

“…PHA-739538 is an aurora kinase inhibitor with strong antiproliferative activity against CD34? cells taken from untreated CML patients and also from imatinib-resistant patients, including those with T315I [93]. A phase II study in patients with CML is now in progress [94].…”