慢性髓系白血病STI571耐药与Bcr-Abl基因点突变的关系

目的通过Bcr-Abl激酶ATP结合区测序分析,探讨慢性髓系白血病(CML)STI571耐药与Bcr-Abl基因点突变的关系。方法将CML患者分为对STI571耐药和非耐药两组,细胞系分为STI571耐药细胞系K562/G01、野生型K562/W细胞,进行骨髓单个核细胞或细胞系细胞Abl基因ATP结合区双向测序分析,了解Abl酪氨酸激酶ATP结合区点突变情况。PCR产物的序列长度为344bp,其中的180bp(98～277bp)为ABL激酶的第906～1085bpDNA序列片段,涵盖了Abl激酶的ATP结合区序列。结果K562/G01耐药细胞ABL激酶ATP结合区DNA测序与K562/W相同,与ABL激酶原序列相比,有两个同义点突变。在STI571耐药急变的CML患者骨髓单个核细胞Abl激酶ATP结合区测序结果发现:在8例耐药急变的患者中2例患者第944位核苷酸C→T单个碱基出现点突变,使苏氨酸(Thr)突变为异亮氨酸(Ile)。1例CML-CP的患者第1070碱基A→G替换,导致357位赖氨酸(Lys)→精氨酸(Arg)。结论Bcr/Abl融合基因ATP结合区的点突变是CML中STI571耐药的重要原因之一,对指导临床用药具有重要价值。     

Second generation Abl kinase inhibitors and novel compounds to eliminate the Bcr-Abl/T315I clone

The first line therapy for chronic myeloid leukemia (CML) was dramatically altered within a few years of the introduction of Abl specific tyrosine kinase inhibitor, imatinib mesylate to the clinic. However, refractoriness and early relapse have frequently been reported, particularly in patients with advanced-stage disease. Point mutations within the Abl kinase domain that interfere with imatinib mesylate binding are most critical cause of imatinib resistance. To override resistance, several second generation ATP competitive Abl kinase inhibitors such as dasatinib, nilotinib and INNO-406 have been developed. Although, these novel inhibitors can inhibit the phosphorylation of most mutated Bcr-Abl except T315I, no ATP competitive Abl kinase inhibitors, which can inhibit the phosphorylation of Bcr-Abl/T315I, has been developed. Thus, Bcr-Abl/T315I is an important and challenging target for discovery of CML therapeutics. This review is focused on the three novel compounds reported in the recent patents (2004-2006) which claim the efficacy against Bcr-Abl/T315I.     

New tyrosine kinase inhibitors in the treatment of chronic myeloid leukemia

Imatinib mesylate, Abl tyrosine kinase inhibitor, has improved the treatment of Bcr-Abl-positive leukemia such as chronic myeloid leukemia (CML) and Philadelphia chromosome positive acute lymphoblastic leukemia (Ph(+)ALL). However, resistance is often reported in patients with advanced-stage disease. Several novel tyrosine kinase inhibitors, which have been developed to override imatinib resistance mechanisms such as overexpression of Bcr-Abl and point mutations within the Abl kinase domain, are currently competing. Inhibitors of Abl tyrosine kinase are divided into two main groups, namely, ATP-competitive and ATP non-competitive inhibitors. Moreover, ATP-competitive inhibitors are fall into two subclasses, i.e. the Src/Abl inhibitors, and 2-phenylaminopyrimidin-based compounds. Dasatinib (formerly BMS-354825), AP23464, SKI-606 and PD166326 are classified as Src/Abl inhibitors while AMN107 and NS-187 (INNO-406) belong to the latter subclass of inhibitors. Among these agents, clinical studies on dasatinib and AMN107 had started earlier than the others and favorable results are accumulating. Clinical studies of other compounds including NS-187 (INNO-406) will be performed in rapid succession. Because of its strong affinity, most ATP competitive inhibitors may be effective against imatinib-resistant patients. However, to date, an ATP-competitive inhibitor that can inhibit the phosphorylation of T315I Bcr-Abl has not yet been developed. To address this problem, ATP non-competitive inhibitors such as ON012380, Aurora kinase inhibitor VX-680 and p38 MAP kinase inhibitor BIRB-796 have been developed. It may be necessary for the improvement of CML and Ph(+)ALL treatment to be taken into consideration of the combination therapy with novel ATP-competitive inhibitors and these agents.     

Structural insights into the conformational selectivity of STI-571 and related kinase inhibitors

STI-571 (Gleevec) is a highly successful cancer drug due to its activity as an inhibitor of the Abelson cytoplasmic tyrosine kinase (Abl), which is constitutively active in a majority of patients with chronic myelogenous leukemia. STI-571 also inhibits two type III receptor tyrosine kinases, c-Kit and platelet-derived growth factor receptor, and functions by targeting inactive conformations of these kinases. This review focuses on recent developments in X-ray co-crystal structure analyses of STI-571 bound to Abl and the c-Kit receptor tyrosine kinase domain, and also three other relevant kinase inhibitor co-crystal structures. The similar structural features of these inactive kinases suggest they will be useful for the successful drug discovery and development of specific and targeted gene-based cancer drugs.     

New Bcr-Abl inhibitors in chronic myeloid leukemia: keeping resistance in check

Targeted therapy with the Abl kinase inhibitor imatinib has markedly improved the outlook for patients with chronic myeloid leukemia (CML). Breakpoint cluster region (Bcr)-Abl signaling is reactivated at the time of resistance, predominantly due to mutations in the kinase domain of Bcr-Abl that interfere with drug binding. This discovery prompted the development of new Abl kinase inhibitors, among which nilotinib and dasatinib have gained regulatory approval. Despite excellent results in patients with imatinib-resistant or imatinib-intolerant CML treated with nilotinib or dasatinib, early indications suggest that: the cross-resistant Bcr-Abl(T315I) mutant is disproportionately represented among patients who relapse on these therapies; each Abl inhibitor exhibits vulnerabilities to certain kinase domain mutations. We review new inhibitors of Bcr-Abl, including preliminary information on inhibitors of Bcr-Abl(T315I) and discuss the potential of combined Abl kinase inhibitor therapy to preempt resistance. Improved Abl inhibitor therapies will be useful in achieving maximum disease control but a clinical T315I inhibitor remains a high priority.     

Preclinical and clinical profile of imatinib mesilate,a potent protein-tyrosine kinase inhibitor for CML therapy

Imatinib mesilate (Glivec) is a protein-tyrosine kinase inhibitor that potently inhibits the Bcr-Abl tyrosine kinase as well as the receptors for platelet-derived growth factor (PDGF) and stem cell factor (SCF), c-Kit, at in vitro and cellular kinase assay levels. Since Bcr-Abl tyrosine kinase plays a key role in chronic myelogenous leukemia (CML) patients, treatment with imatinib mesilate that potently inhibits Bcr-Abl tyrosine kinase could be a promising therapeutic approach to CML. Imatinib mesilate was shown to inhibit proliferation of bcr-abl-positive cell lines and suppress the formation of bcr-abl-positive colonies in cells derived from bone marrow of CML patients. This compound induced apoptosis in a variety of bcr-abl-positive cells. Moreover, in vivo data indicated that imatinib mesilate suppress growth and formation of bcr-abl-positive tumors in mice. As the profile expected from the preclinical studies, imatinib mesilate showed impressive hematological and cytogenic responses in the clinical trials, including interferon-alpha-resistant or intolerant patients.     

Mechanisms of resistance to imatinib (STI571) and prospects for combination with conventional chemotherapeutic agents.

Imatinib (STI571, Glivec) is a small molecule drug selected for its ability to inhibit the Bcr-Abl kinase, the pathogenic molecular abnormality in chronic myelogenous leukemia (CML). It also is an efficient inhibitor of the Kit and platelet-derived growth factor receptor tyrosine kinases. In vitro studies have demonstrated that this drug potently inhibits proliferation and induces apoptosis of cells that depend on activation of these kinases. Phase I clinical studies have demonstrated remarkable activity against CML. However, these studies, as well as a variety of experimental models, have suggested that clinical resistance to STI571 could develop. The mechanisms for the development of this resistance will be discussed along with the potential for circumventing STI571 resistance by combining it with traditional anti-neoplastic agents.     

Bafetinib, a dual Bcr-Abl/Lyn tyrosine kinase inhibitor for the potential treatment of leukemia

Bafetinib (NS-187, INNO-406) is a second-generation tyrosine kinase inhibitor in development by CytRx under license from Nippon Shinyaku for treating Bcr-Abl+ leukemia's, including chronic myelogenous leukemia (CML) and Philadelphia+ acute lymphoblastic leukemia. It is a rationally developed tyrosine kinase inhibitor based on the chemical structure of imatinib, with modifications added to improve binding and potency against Bcr-Abl kinase. Besides Abl, bafetinib targets the Src family kinase Lyn, which has been associated with resistance to imatinib in CML. In preclinical studies, bafetinib was 25- to 55-fold more potent than imatinib in vitro and ≥ 10-fold more potent in vivo. Bafetinib inhibits 12 of the 13 most frequent imatinib-resistant Bcr-Abl point mutations, but not a Thr315Ile mutation. A small fraction of bafetinib crosses the blood-brain barrier, reaching brain concentrations adequate for suppression of Bcr-Abl+ cells. Data from a phase I clinical trial conducted in patients with imatinib-resistant or -intolerant CML have confirmed that bafetinib has clinical activity in this setting, inducing a major cytogenetic response in 19% of those patients in chronic phase. Currently, bafetinib is being developed in two phase II clinical trials for patients with B-cell chronic lymphocytic leukemia and prostate cancer, and a trial is in progress for patients with brain tumors.     

New Bcr-Abl inhibitors in chronic myeloid leukemia: keeping resistance in check

Targeted therapy with the Abl kinase inhibitor imatinib has markedly improved the outlook for patients with chronic myeloid leukemia (CML). Breakpoint cluster region (Bcr)-Abl signaling is reactivated at the time of resistance, predominantly due to mutations in the kinase domain of Bcr-Abl that interfere with drug binding. This discovery prompted the development of new Abl kinase inhibitors, among which nilotinib and dasatinib have gained regulatory approval. Despite excellent results in patients with imatinib-resistant or imatinib-intolerant CML treated with nilotinib or dasatinib, early indications suggest that: the cross-resistant Bcr-Abl^T315I mutant is disproportionately represented among patients who relapse on these therapies; each Abl inhibitor exhibits vulnerabilities to certain kinase domain mutations. We review new inhibitors of Bcr-Abl, including preliminary information on inhibitors of Bcr-Abl^T315I and discuss the potential of combined Abl kinase inhibitor therapy to pre-empt resistance. Improved Abl inhibitor therapies will be useful in achieving maximum disease control but a clinical T315I inhibitor remains a high priority.     

Growth inhibition of rat osteosarcoma and malignant fibrous histiocytoma cells by tyrosine kinase inhibitor STI571

STI571 is a 2-phenylaminopyrimide derivative that was designed as an Abl tyrosine kinase inhibitor, but it is also effective against platelet-derived growth factor receptor (PDGFR) and c-Kit tyrosine kinase. Recent studies have demonstrated that STI571 inhibits the growth of several tumors in which PDGF or c-kit play an important role in tumor pathogenesis. We have recently established rat osteosarcoma and malignant fibrous histiocytoma (MFH) cell lines. RT-PCR analysis revealed that MFH and osteosarcoma cell lines expressed high and very low levels of PDGFR alpha respectively, and that all cell lines expressed similar levels of PDGFR beta. The level of c-kit mRNA expression were almost negligible hardly in all cell lines. The effect of STI571 on cellular growth measured by MTS colorimetric dye reduction showed that the growth of each cell line was inhibited in a dose- and time-dependent manner. STI571 (10 microM) inhibited the rates of cell growth of MFH cells by up to 40% and of osteosaroma cells by only to 20% after 72 hours. These data suggested that STI571 tyrosine kinase inhibitor plays a role in blocking or slowing the rate of growth of MFH and osteosarcoma cells expressing tyrosine kinase type receptor.     

Imatinib (STI571) resistance in chronic myelogenous leukemia: molecular basis of the underlying mechanisms and potential strategies for treatment

Following the paradigm set by STI571, protein tyrosine kinase inhibitors are emerging as a promising class of drugs, capable of modulating intracellular signaling and demonstrating therapeutic potential for the treatment of proliferative diseases. Although the majority of chronic phase CML patients treated with STI571 respond, some patients, especially those with more advanced disease, relapse. This article reviews the reasons for relapse and, in particular, analyses resistance resulting from Bcr-Abl tyrosine kinase domain mutations at the molecular level. Arguments are based upon the structure of the STI571-Abl complex, which is compared to the crystal structures of PD173955-Abl and PD180970-Abl, which bind to the kinase differently. Strategies to potentially circumvent or overcome resistance are discussed.     

Imatinib mesylate (Gleevec,Glivec): a new therapy for chronic myeloid leukemia and other malignancies

Imatinib mesylate (STI571, Gleevec, Glivec, a selective inhibitor of the BCR-ABL tyrosine kinase causative of chronic myeloid leukemia (CML), represents the paradigm of how a better understanding of the pathogenetic mechanisms of a neoplastic disease can lead to the development of a targeted molecular therapy. Phase II clinical trials have shown marked therapeutic activity of imatinib in all evolutive phases of CML, but notably in the chronic phase, where it induces complete hematological responses in almost 100% of patients resistant or intolerant to interferon, with a major cytogenetic response rate of 60%, including 41% complete cytogenetic responses. The preliminary results of an ongoing phase III multicenter randomized study comparing imatinib with interferon plus cytarabine as first-line treatment for CML favor imatinib in terms of efficacy and safety. If confirmed with longer follow-up,these results would establish imatinib as the choice therapy for the majority of CML patients, with allogeneic transplantation being restricted as initial therapy only to younger patients with a family donor. Longer follow-up will answer some questions, such as those on long-term safety, durability of the responses, whether these will translate into a survival prolongation and the possibility of molecular responses. In addition, further information on the mechanisms involved in the primary and acquired resistance to imatinib is needed. Besides the Bcr-Abl protein, the drug is also active against other tyrosine kinases, such as Abl, the stem-cell factor receptor (c-kit) and the platelet-derived growth factor receptor, whose inhibition might have potential implications for the treatment of several malignancies. In this sense, it must be pointed out that imatinib has shown a remarkable activity in gastrointestinal stromal tumors.     

The novel pyrrolo-1,5-benzoxazepine, PBOX-21, potentiates the apoptotic efficacy of STI571 (imatinib mesylate) in human chronic myeloid leukaemia cells

The Bcr-Abl kinase inhibitor, STI571, is the first line treatment for chronic myeloid leukaemia (CML), but the recent emergence of STI571 resistance has led to the examination of combination therapies. In this report, we describe how a novel non-toxic G1-arresting compound, pyrrolo-1,5-benzoxazepine (PBOX)-21, potentiates the apoptotic ability of STI571 in Bcr-Abl-positive CML cells. Co-treatment of CML cells with PBOX-21 and STI571 induced more apoptosis than either drug alone in parental (K562S and LAMA84) and STI571-resistant cells lines (K562R). This potentiation of apoptosis was specific to Bcr-Abl-positive leukaemia cells with no effect observed on Bcr-Abl-negative HL-60 acute myeloid leukaemia cells. Apoptosis induced by PBOX-21/STI571 resulted in activation of caspase-8, cleavage of PARP and Bcl-2, upregulation of the pro-apoptotic protein Bim and a downregulation of Bcr-Abl. Repression of proteins involved in Bcr-Abl transformation, the anti-apoptotic proteins Mcl-1 and Bcl-_XL was also observed. The combined lack of an early change in mitochondrial membrane potential, release of cytochrome c and cleavage of pro-caspase-9 suggests that this pathway is not involved in the initiation of apoptosis by PBOX-21/STI571. Apoptosis was significantly reduced following pre-treatment with either the general caspase inhibitor Boc-FMK or the chymotrypsin-like serine protease inhibitor TPCK, but was completely abrogated following pre-treatment with a combination of these inhibitors. This demonstrates the important role for each of these protease families in this apoptotic pathway. In conclusion, our data highlights the potential of PBOX-21 in combination with STI571 as an effective therapy against CML.     

Drug evaluation: Nilotinib - a novel Bcr-Abl tyrosine kinase inhibitor for the treatment of chronic myelocytic leukemia and beyond

Chronic myelocytic leukemia (CML) is caused by the constitutively active tyrosine kinase Bcr-Abl. Inhibitors ofBcr-Abl have significantly improved the treatment of CML. Most notable is the inhibitor imatinib, which produces remissions in all phases of CML and is the current standard of care. However, imatinib resistance occurs in a significant proportion of patients, mainly through the development of mutations in the Bcr-Abl tyrosine kinase domain that impair imatinib binding. Attempts to circumvent resistance to imatinib led to the discovery of nilotinib (Tasigna; Novartis AG), a novel, potent and selective oral Bcr-Abl kinase inhibitor. Preclinical and clinical investigations have demonstrated that nilotinib effectively overcomes imatinib resistance. Efficacy has been observed in models of CML and other myeloproliferative disorders that are driven by Bcr-Abl and related kinases. In a phase II clinical trial in CML, major cytogenetic response rates were 52 and 33% for chronic- and accelerated-phase disease, respectively. Nilotinib has been filed for approval in the US and EU for use in Philadelphia-positive leukemias in patients who are resistant or intolerant to imatinib. Nilotinib is undergoing clinical trials in patients with newly diagnosed CML, acute lymphoblastic leukemia and gastrointestinal stromal tumors, among other indications.     

STI571 and morpholine derivative of doxorubicin collaborate in inhibition of K562 cell proliferation by inducing differentiation and mitochondrial pathway of apoptosis

Differentiation therapy is considered as a supplementary approach to the currently applied treatments for leukemia. We have previously shown that a morpholine derivative of doxorubicin (DOXM) appeared to be a more efficient inducer of erythroid differentiation of K562 cells than the parent drug [Czyz, M., Szulawska, A., Bednarek, A.K., Duchler, M., 2005. Effects of anthracycline derivatives on human leukemia K562 cell growth and differentiation. Biochem. Pharmacol. 70, 1431-1442.; Szulawska, A., Arkusinska, J., Czyz, M., 2007. Accumulation of gamma-globin mRNA and induction of irreversible erythroid differentiation after treatment of CML cell line K562 with new doxorubicin derivatives. Biochem. Pharmacol. 73, 175-184.]. In the current study we used this compound in combination with STI571, a front-line drug in therapy of chronic myelogenous leukemia (CML), to evaluate possible benefits of the combined treatment on the cellular level. Using K562 cells, we analyzed the response of CML cells to low concentrations of DOXM when Bcr-Abl activity was reduced to various levels by its specific inhibitor, STI571. Differentiation was significantly enhanced with the combination of 150 nM STI571 and 100 nM DOXM as compared to the levels obtained with either drug alone. A higher concentration of STI571 was required to diminish Bcr-Abl activity to the level which was sufficient to stimulate apoptotic cell death pathway in K562. Apoptosis induced by 250 nM STI571 was markedly enhanced by DOXM in the combined treatment. Mitochondrial transmembrane potential dissipation and translocation of phosphatydylserine to the outer plasma membrane were increased by 50%. Our results clearly indicate that differentiation and apoptosis, both reducing cellular proliferation, could be substantially enhanced by the combined treatment. We provide experimental evidence implicating that the diversification of cellular effects obtained in the combined treatment employing non-toxic approaches to enhance efficacy of STI571 might be considered as an alternative therapeutic strategy against CML, especially for apoptosis-reluctant cells.     

Structural Analysis of DFG-in and DFG-out Dual Src-Abl Inhibitors Sharing a Common Vinyl Purine Template

Bcr-Abl is the oncogenic protein tyrosine kinase responsible for chronic myeloid leukemia (CML). Treatment of the disease with imatinib (Gleevec) often results in drug resistance via kinase mutations at the advanced phases of the disease, which has necessitated the development of new mutation-resistant inhibitors, notably against the T315I gatekeeper mutation. As part of our efforts to discover such mutation resistant Abl inhibitors, we have focused on optimizing purine template kinase inhibitors, leading to the discovery of potent DFG-in and DFG-out series of Abl inhibitors that are also potent Src inhibitors. Here we present crystal structures of Abl bound by two such inhibitors, based on a common N9-arenyl purine, and that represent both DFG-in and -out binding modes. In each structure the purine template is bound deeply in the adenine pocket and the novel vinyl linker forms a non-classical hydrogen bond to the gatekeeper residue, Thr315. Specific template substitutions promote either a DFG-in or -out binding mode, with the kinase binding site adjusting to optimize molecular recognition. Bcr-Abl T315I mutant kinase is resistant to all currently marketed Abl inhibitors, and is the focus of intense drug discovery efforts. Notably, our DFG-out inhibitor, AP24163, exhibits modest activity against this mutant, illustrating that this kinase mutant can be inhibited by DFG-out class inhibitors. Furthermore our DFG-out inhibitor exhibits dual Src-Abl activity, absent from the prototypical DFG-out inhibitor, imatinib as well as its analog, nilotinib. The data presented here provides structural guidance for the further design of novel potent DFG-out class inhibitors against Src, Abl and Abl T315I mutant kinases.     

Mechanisms of resistance imatinib (STI571) in preclinical models and in leukemia patients.

The tyrosine kinase inhibitor imatinib (STI571, Glivec) blocks the activity of the BCR/ABL oncogene and induces hematologic remissions in the majority of patients with chronic myeloid leukemia (CML). Glivec is an aminopyrimidine derivative that interacts with the ATP-binding site within the kinase domain of ABL and several other tyrosine kinases, including c-KIT, PDGF beta receptor, and ARG. The compound is currently in phase III clinical trials. Although patients with chronic phase CML have been found to develop drug resistance only rarely so far, patients in more advanced phases of the leukemia develop resistance frequently. The available information on Glivec resistance will be reviewed.     

Relationship between elevated levels of the alpha 1 acid glycoprotein in chronic myelogenous leukemia in blast crisis and pharmacological resistance to imatinib (Gleevec) in vitro and in vivo

The Abl tyrosine kinase inhibitor imatinb is becoming a standard for the treatment of chronic myelogenous leukemia (CML). However, Bcr-Abl gene mutations have been reported mainly in relapsing or resistant patients. In primary resistant patients, only few mutations have been documented so far, suggesting alternative mechanisms. We aimed to investigate if alpha 1 acid glycoprotein (AGP), an acute phase drug binding protein, could be a biological marker for pharmacological resistance to imatinib in nine patients in acute phase CML. All patients (3/3) with high AGP dosages (2.31+/-0.17 mg/mL; normal values, 0.5-1.3mg/mL) were primary resistant to imatinib whereas an early clinical response was observed for the six patients with normal AGP levels (1.13+/-0.2mg/mL). No mutation in the adenosine triphosphate domain of Abl were detected before the initiation of imatinib therapy. By using in vitro tests combining various imatinib concentrations (1-10 microM) with purified human AGP (1 and 3 mg/mL), we demonstrate that imatinib-induced apoptosis of K562 or fresh leukemic CML cells is abrogated or reduced. The same effect was observed using sera from donors with high AGP levels (1.9-3.28 mg/mL). In patients with CML in blastic phase, AGP levels could reflect pharmacological resistance to imatinib, suggesting that increased dosage of imatinib or the use of a competitor to drug binding should be recommended to optimize the therapeutic effect of the drug.     

针对T315I突变的Bcr—Abl酪氨酸激酶抑制剂研究进展

BCR-ABL是一种由bcr基因和c-abl原癌基因融合产生的致癌基因。该基因表达的Bcr-Abl癌蛋白是慢性粒细胞白血病的病理学基础。因此研发选择性的Bcr-Abl酪氨酸激酶抑制剂成为治疗慢性粒细胞白血病的一种有效策略。目前已有数个Bcr-Abl酪氨酸激酶抑制剂获准上市。然而,Abl激酶结构域的突变或其他原因导致肿瘤耐药性的出现,其中T315I突变是最重要的突变之一,引发的耐药性更是难以克服。重点介绍了针对T325I突变的Bcr-Abl酪氨酸激酶抑制剂的研究进展。     

Pigmentary changes in a patient treated with imatinib

Imatinib mesylate (STI 571; Gleevec; Novartis Pharmaceuticals, Basel, Switzerland) is an orally available tyrosine kinase inhibitor that targets a constitutively activated BCR-ABL tyrosine kinase with additional inhibitory effects on platelet derived growth factor (PDGF) receptors alpha and beta, and KIT. It has revolutionized the treatment of adult and pediatric patients with Philadelphia chromosome positive chronic myelogenous leukemia (CML) and is also FDA-approved for KIT-positive advanced gastrointestinal tumor (GIST) and dermatofibrosarcoma protuberans. A wide spectrum of dermatologic toxicities has been associated with this agent, among which a maculopapular rash is the most common event. In addition, a variety of pigmentary abnormalities of the skin and mucosal surfaces have been reported. Hypopigmentation is a well-recognized adverse effect. In contrast, paradoxical hyperpigmentation has only rarely been documented. In this case report we describe imatinib-induced cutaneous hyperpigmentation and graying of hair occurring in the same patient with dermatofibrosarcoma protuberans treated with imatinib.