Imatinib-resistant chronic myeloid leukemia (CML): Current concepts on pathogenesis and new emerging pharmacologic approaches

Figures & data

Figure 1 Evolution of CML with prephases—a proposed hypothesis.

Abbreviations: Ph, Philadelphia chromosome; CML, chronic myeloid leukemia; AML, acute myeloid leukemia.

Table 1 Resistance of CML stem cells against imatinib: Proposed hypotheses*

Observations	Specific hypothesis/ molecular basis
Stem cell quiescence (dormance)	G0 arrest by chalones or by specific cell cycle regulators, quite similar mechanisms may lead to dormance of normal stem cells**
Stem cell plasticity	Development of subclones may be facilitated by mechanisms similar to those responsible for differentiation of normal myeloid stem cells into various myeloid lineages** – exact mechanisms are unknown
Overexpression of BCR/ABL	BCR/ABL mRNA and protein over- expression – mechanisms unknown
Specific BCR/ABL-induced stem cell deregulation	Altered DNA repair; hypermethylation; induction of stem cell subclones. Over time, BCR/ABL may overcome some of the stem cell-protecting mechanisms
BCR/ABL-independent survival	Stem cell-specific survival factors; altered survival factors in subclones***
Decreased uptake of imatinib	Decreased expression of OCT-1, a major transporter of imatinib
Increased drug efflux	Overexpression of P-glycoprotein(MDR-1) and other efflux pumps****

Notes:

* Relate all to differences between CML stem cells and more mature CML cells. The following articles refer to these concepts: Copland et al 2005, ²⁰⁰⁶; Barnes and Melo 2006; Brendel et al 2007; Jiang et al 2007b);

** The biology of normal stem cells and CML stem cells may be quite similar;

*** CML stem cells may even survive after complete deactivation of BCR/ABL;

**** Normal and neoplastic stem cells may defend their long-term existence against external ‘enemies’ (toxins, drugs) by high toxin/drug efflux.

Abbreviations: OCT-1, organic cation transporter; MDR-1, multidrug resistance gene-1.

Table 2 BCR/ABL mutations detectable in CML patients treated with imatinib

Mutant	IC50* imatinib	may benefit from IM-dose-escalation**	IC50* dasatinib	IC50* nilotinib
no (wt)	250–500	-	0.8	13
M244V	1,600–3,100	yes	1.3	38
M244I	1,400	yes	nk	nk
G250E	>1,000 (>3,000)	no	1.8	48
Q252H	1,300–2,900	yes	3.4	70
Y253H	4,000–17,000	no	1.3	450
Y253F	1,800–5,000	no	1.4	125
E255K	5,000–12,000	no	5.6	200
E255V	6,000–20,000	no	11	430
F311L	480–1,300	no	1.3	23
T315I	>10,000	no	>200	>2,000
F317L	1,000–2,300	no	7.4	50
M351T	900–4,900	yes	1.1	15
M351I	1,600	yes	nk	nk
F359V	1,400–1,800	yes	2.2	175
E355G	2,000–2,400	yes	nk	nk
V379I	1,000–1,600	yes	0.8	51
L387M	1,000–1,100	yes	2	49
H396P	850–4,300	no	0.6	41
H396R	1,750–5,400	no	1.3	41

Notes:

* IC50 values are given in nM and refer to published data obtained with Ba/F3 cells exhibiting wild type BCR/ABL or various BCR/ABL mutants using cell – proliferation assays (O’Hare et al 2005; Martinelli et al 2005);

** recommendations are derived from Martinelli and colleagues (2005).

Abbreviations: IM, imatinib; wt, wild type; nk, not known.

Table 3 Novel pharmacologic inhibitors proposed for imatinib-resistant CML

Drug name	Drug type class	Known target(s)	active in cells bearing BCR/ABL T315I
Dasatinib (Sprycel)	TKI	Abl, Src, Lyn, Btk, Kit, PDGFR,	no
Nilotinib (Dasigna)	TKI	Abl, Kit, PDGFR, ......	no
SKI-606 (Bosutinib)	TKI	Abl, Src, ..	no
INNO-406 (NS-187)	TKI	Abl, Lyn, Kit, ..	no
AZD0530	TKI	Abl, Src, ..	no
AP23464	TKI	Abl, Src, ..	no
CGP76030	TKI	Abl, Src, ..	+/−*
PP1	TKI	Abk, Src, ..	+/−*
PD166326	TKI	Abl, Src, ..	no
ON012380	TKI	Abl, PDGFR, Lyn	yes
MK-0457 (VX-680), other AuK-I	AuK-I	Aurora-kinase	yes
BIRB-796, 43-9006 (sorafenib)	p38-I	p38 MAP kinase, (Abl)	no
	Kinase-I	multiple kinases, Mcl-1	yes
WP1130	-	? (Jak, Abl-knock-down)	yes
various	hypomethylating agents	re-expression of tumor suppressors	+/−
various	Hsp-I	Hsp32, Hsp70, Hsp90, …	yes
various compounds	FTIs	RAS	+/−
various compounds	PI3K-I	PI3-kinase	yes
Rapamycin and its derivatives	mTOR-I	mTOR	yes

Notes:

* relatively high drug concentrations needed to block growth of cells.

Abbreviations: TKI, tyrosine kinase inhibitor; PDGFR, platelet derived growth factor receptor; Hsp, heat shock proteins; FTI, farnesyl transferase inhibitor; mTOR, mammalian target of rapamycin.

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