The MEK inhibitor PD184352 enhances BMS-214662-induced apoptosis in CD34+ CML stem/progenitor cells

Abstract

The cytotoxic farnesyl transferase inhibitor BMS-214662 has been shown to potently induce mitochondrial apoptosis in primitive CD34+ chronic myeloid leukaemia (CML) stem/progenitor cells. Here, to enhance the BMS-214662 apoptotic effect, we further targeted the RAS-MEK-ERK pathway, downstream of BCR-ABL, by treating CD34+ CML stem/progenitor cells with a highly selective ATP non-competitive MEK inhibitor, PD184352. PD184352 increased the apoptotic effect of BMS-214662 in a CML blast crisis cell line, K562, and in primary chronic phase CD34+ CML cells. Compared to BMS-214662, after combination treatment we observed inhibition of ERK phosphorylation, increased Annexin-V levels, caspase-3, 8 and 9 activation and potentiated mitochondrial damage, associated with decreased levels of anti-apoptotic BCL-2 family protein MCL-1. Inhibition of K-RAS function by a dominant negative mutant resulted in CML cell death and this process was further enhanced by the addition of BMS-214662 and PD184352. Together, these findings suggest that the addition of a MEK inhibitor improves the ability of BMS-214662 to selectively target CML stem/progenitor cells, notoriously insensitive to tyrosine kinase inhibitor treatment and presumed to be responsible for the persistence and relapse of the disease.

Natural course and biology of CML

“…Disruption of Ras signalling impairs development of BCR-ABL1-induced CML-like disease in mice [60,68]. In addition, small molecule inhibitors against MEK can target primitive CML cells [69,70]. However, there is limited knowledge of how the Ras-effector repertoire contributes to disease, and which effectors in particular are important.…”

How I treat CML blast crisis

“…87,88 The MEK inhibitor PD184352 combined with the farnesyltransferase inhibitor BMS-214662 similarly induces apoptosis in K562 cells and CD34 ϩ CML stem cells. 89 In addition, p53 stabilization with the novel compound MI-219, which inhibits human homolog double minute 2, induces apoptosis in cell line and primary BC cells. 90 And recently, the dual Jak2/Abl kinase inhibitor ON044580 was shown to induce apoptosis in cells from BC patients and in imatinibresistant cells, including T315I.…”

Update on emerging treatments for chronic myeloid leukemia

“…Among signaling transduction inhibitors, MEK inhibitors have been reported to play a potential role both in the regulation of CML cellular proliferation and in mediating resistance to apoptosis [88,89]. One compound, MEK 162, is under investigation in association with nilotinib in advanced CML (NCT02225574 , Table 3).…”