Abstract 1993: BMS-354825 kills quiescent CML cells in vitro

[Guest guest]

In this morning's post on IM pulse therapy, I wrote that I knew of no second

drug on the horizon that could be used in combination with IM (or dasatinib

or AMN107) to kill all CML cells including the quiescent ones. I had

forgotten about this ASH poster session/abstract, whose conclusion is that

the farnesyl transferase inhibitor (FTI), BMS-354825, kills quiescent CML

cells at surprisingly low concentrations of the drug. In fact, BMS-214662 is

68 times more potent against quiescent cells than against cycling cells -

the exact opposite of all the other drugs in trial right now. This study was

done in vitro (in the test tube, that is), not in humans, but these authors

claim that a BMS-354825 Phase I clinical trials (see

http://www.clinicaltrials.gov/ct/show/NCT00064233) is already underway.

The fact that its targets (farnesyl transferase - and quiescent cells) and

its mechanism of action differ from those of IM, etc., potentially make it

the ideal drug to be used in combination with one of the others. A compound

to keep an eye on, for sure.

Cheers,

R

____________________

[1993] Quiescent Chronic Myelogenous Leukemia (CML) Cells Are Resistant to

BCR-ABL Inhibitors but Preferentially Sensitive to BMS-214662, a

Farnesyltransferase Inhibitor (FTI) with Unique Quiescent-Cell Selective

Cytotoxicity. Session Type: Poster Session 197-II

Francis Y. Lee, Mei-Li Wen, Amy Camuso, Castenada, Krista Fager,

Flefleh, Ivan Inigo, Luo, Kan, Veeraswamy Manne,

McGlinchey, Smykla, o Weinmann, Kramer (Intr. by

Mullaney). Oncology, Bristol-Myers Squibb Co., Princeton, NJ, USA

The major concern in the treatment of CML is resistance to the approved

agent imatinib mesylate at all stages of disease, most commonly due to

mutations in BCR-ABL (but other mechanisms have also been identified).

Experimental agents such as dasatinib (BMS-354825), a novel, oral kinase

inhibitor that targets BCR-ABL and SRC kinases, or AMN107, which targets

BCR-ABL but not SRC, were designed to address all or parts of these

mechanisms and are currently under clinical testing. A second concern in CML

is persistence of BCR-ABL­positive cells or 'residual disease' in the

majority of patients on imatinib therapy, including those with complete

cytogenetic responses. Bone marrow studies reveal that the residual disease

resides at least in part in the primitive CD34+ progenitor compartment,

suggesting that imatinib may not be effective against these cell populations

(Bhatia et al, Blood 101:4701, 2003). Moreover, several imatinib-resistant

ABL kinase domain mutations have been detected in CD34+/BCR-ABL+ progenitors

(Chu et al, Blood 105:2093, 2005), a scenario for eventual disease relapse.

A hallmark of CD34+ primitive CML progenitors is quiescence (Elrick et al,

Blood 105:1862, 2005). We hypothesized that BCR-ABL inhibitors like imatinib

may not be effective in killing CML cells in this non-proliferative state.

This was tested by comparing cytotoxicity of imatinib or dasatinib in

proliferating K562 cells and in cells forced into quiescence by nutrient

depletion. Proliferating K562 cells were effectively killed by imatinib

(IC50 250­500 nM) and dasatinib (IC50 <1.00 nM). However, cells in quiescent

cultures were far more resistant (imatinib IC50 >5000 nM; dasatinib IC50 >12

nM), suggesting that these inhibitors may be less effective in eradicating

quiescent CD34+ progenitors. BMS-214662 is a FTI in Phase I clinical

development. Unlike many other FTI, BMS-214662 exhibits potent cytotoxic

activity against a variety of human tumor cells, and uniquely, its

cytotoxicity is highly selective against non-proliferating cancer cells of

epithelial origin (Lee et al, Proceedings of the AACR 42:260s, 2001). We now

demonstrate similar selectivity in K562 CML cells. BMS-214662 was 68-fold

more potent in killing quiescent (IC50 = 0.7 uM) than proliferating K562

cells (IC50 = 47.5 uM). Because BCR-ABL inhibitors and BMS-214662 target

distinct cell populations (proliferating vs quiescent), there may be a

positive therapeutic interaction when these agents are used in combination.

In vitro studies in quiescent K562 cultures demonstrated that the

combination of BMS-214662 and dasatinib, at concentrations readily

achievable in the clinic, produced supra-additive cytotoxicity (% cell kill:

dasatinib alone = 0%, BMS-214662 alone = 21%, combination = 71%). In vivo

studies in K562 xenografts implanted SC in mice also showed that the

combination of BMS-214662 and dasatinib produced a superior anti-leukemic

activity than either dasatinib alone (P=0.0157) or BMS-214662 alone

(P=0.0002). These results highlight the potential utility of BMS-214662 for

targeting the quiescent progenitor compartment which, in combination with

targeted agents such as dasatinib, address both BCR-ABL­dependent and

­independent mechanisms of resistance, and may produce more durable

responses and suppress the emergence of resistance.