Although imatinib and other tyrosine kinase inhibitors (TKIs) achieve high response rates in patients with chronic myeloid leukemia (CML), patients can fail these therapies or develop specific mutations that render TKIs ineffective. Moreover, TKIs have limited effectiveness against CML cancer stem cells (CSCs). It was previously shown that SL-401, a novel targeted therapy directed to the interleukin 3 receptor (IL-3R), inhibits the growth of CML tumor bulk and CSCs, both of which over express IL-3R. SL-501 is a next-generation targeted therapy also directed to IL-3R. SL-501 has approximately 4-fold increased binding affinity for IL-3R and a more than 30-fold increase in potency against acute myeloid leukemia (AML) cells compared to SL-401. In this study, we assessed the activity of SL-501 against a panel of TKI-sensitive and TKI-resistant CML cell lines. KBM5, KBM5-STI, K562, and BV173 cells were treated with SL-501 (range: 5 - 21,000 pg) for 24 or 48 hours and assessed for viability and apoptosis. We found that SL-501 reduced the absolute cell number of all cell lines tested in a dose-dependent manner with IC50s of 20 pM, 21 pM, 31.5 nM, and 3.9 nM, respectively; these concentrations are readily achieved at tolerable doses in the clinic. Moreover, SL-501 significantly reduced the number of imatinib-resistant KBM5-STI viable cells by more than 5-fold after 48 hours. Using caspase and lactate dehydrogenase (LDH) release assays, we also found that SL-501 alone induced apoptosis of all cell lines tested by more than 40% after 24 hours. The combination of SL-501 with TKIs (imatinib, dasatinib, or nilotinib) had an enhanced effect on apoptosis in KBM5, K562, and BV173 cells 24 hours post-treatment. Taken together, these findings indicate that SL-501, a novel next-generation IL-3-targeted therapeutic, may be effective at treating TKI-resistant CML. These promising results together with the IL-3R expression pattern on CML blasts and CSCs warrant further development of SL-501 in CML and, in particular, TKI-resistant CML.
Citation Format: Christopher Brooks, Kenneth Hoberman, Ivan Bergstein, Eric Rowinsky. SL-501, a next-generation targeted therapy directed to IL-3R, inhibits the growth of tyrosine kinase inhibitor-resistant CML cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4507. doi:10.1158/1538-7445.AM2014-4507