Abstract 3604: Targeting the PIM kinases in combination with BTK inhibition is synergistic in preclinical models of B-cell malignancies

Abstract

Abstract BTK inhibitors (e.g. ibrutinib) have significantly impacted the treatment of B-cell malignancies in a positive way. Single agent response rates with ibrutinib are 65% or higher in B-cell lymphomas and chronic lymphocytic leukaemia with the majority of patients enjoying a prolonged duration of response. Continued clinical development is needed, however, as most patients achieve only a partial response from their treatment and ultimately patients become refractory to ibrutinib leading to relapse and disease progression. Targeted combinations with ibrutinib could potentially increase the number of patients undergoing complete remission and combat emergent resistant mechanisms. The PIM family (1, 2, and 3) are serine/threonine kinases that have proven to be oncogenic in-part due to their ability to suppress c-Myc induced apoptosis. The PIM kinases have emerged as important regulators of drug resistance in multiple cancer types. Tolero Pharmaceutical's second generation PIM Kinase inhibitor, TP-3654 has exhibited favorable activity in preclinical models of prostate cancer, AML, and lymphoma. Due to the signaling crosstalk between BTK and PIM through the STAT transcription factors, we hypothesized that synergies may arise through the simultaneous targeting of both kinases. Here, we report a significant increase in drug activity when a BTK inhibitor (ibrutinib) was combined with TP-3654 in various lymphoma cell lines. In Granta-519 cells, the IC50 of ibrutinib decreased 3.5-fold, from 0.7 μM to 0.2 μM, when cultured in combination with a subtoxic concentration of TP-3654 (300 nM). Similarly, the IC50 of TP-3654 decreased 6-fold, from 2.4 μM to 0.4 μM, when cells were cultured in combination with a subtoxic concentration of ibrutinib (100 nM). BTK is known to attenuate the activity of the transcription factor STAT3, a major regulator of PIM kinase levels in cells. Due to this, mechanistic studies focused on analyzing the STAT3 pathway are ongoing to determine the downstream effects of using ibrutinib and TP-3654 in combination. Several lymphoma xenograft studies are also ongoing to further explore this combination in vivo. These results provide a strong rationale that inhibitors of PIM and BTK could be used in combination for the treatment of B-cell malignancies and other B-cell mediated diseases. Citation Format: Jeremiah J. Bearss, Brigham L. Bahr, Katie K. Soh, Peter W. Peterson, Clifford J. Whatcott, Adam Siddiqui-Jain, David J. Bearss, Steven L. Warner. Targeting the PIM kinases in combination with BTK inhibition is synergistic in preclinical models of B-cell malignancies. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3604. doi:10.1158/1538-7445.AM2015-3604