Defining and Managing Imatinib Resistance

Mauro, Michael J.

doi:10.1182/asheducation-2006.1.219

Cited by 71 publications

(38 citation statements)

References 42 publications

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“…In patients receiving Imatinib for chronic myelogenous leukemia, for example, resistance emerges often [49]. Further understanding of the mechanisms involved in drug resistance will be crucial to the effective treatment of patients with MTC.…”

Section: Ongoing Challenges and Unmet Needsmentioning

confidence: 99%

RET oncogene in MEN2, MEN2B, MTC and other forms of thyroid cancer

Lodish¹,

Stratakis²

2008

Expert Review of Anticancer Therapy

105

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SummaryHereditary medullary thyroid carcinoma (MTC) is caused by specific autosomal dominant gain-of function mutations in the RET proto-oncogene. Genotype-phenotype correlations exist that help predict the presence of other associated endocrine neoplasms as well as the timing of thyroid cancer development. MTC represents a promising model for targeted cancer therapy, as the oncogenic event responsible for initiating malignancy has been well characterized. The RET proto-oncogene has become the rational target for molecularly designed drug therapy. Tyrosine kinase inhibitors targeting activated RET are currently in clinical trials for the treatment of patients with MTC. This review will provide a brief overview of MTC and the associated RET oncogenic mutations, as well as a summary of the therapies designed to strategically interfere with pathologic activation of the RET oncogene. KeywordsMultiple endocrine neoplasia; tyrosine kinase inhibitors; thyroid cancer; oncogenes; clinical trial Introductory overview of the disease: epidemiology and pathophysiologyThyroid cancer represents approximately 1% of malignancies occurring in the United States, accounting for an estimated 33,550 cancer diagnoses and 1,530 cancer deaths per year. Of these cancers, 2% to 3% are due to medullary thyroid cancer (MTC) [1]. MTC is a rare calcitoninproducing tumor that arises from the thyroid gland parafollicular C cells, which are derived from the embryonic neural crest. While the majority of patients with MTC have sporadic disease, 25% to 30% of cases are due to hereditary forms of MTC [2]. The presentation of disease in hereditary MTC is usually bilateral and multicentric, compared with a single, unilateral thyroid tumor found in sporadic cases [3].Hereditary MTC is classified according to three distinct clinical subtypes (Table 1 Summary of current optimal therapeutic practicesMTC is relatively unresponsive to radiation therapy and to standard chemotherapeutic regimens [8,9]. Various chemotherapeutic regimens, including alkylating agents, antimetabolites, and anthracyclines have shown no proven benefit in patients with metastatic MTC [10][11][12]. Radiation therapy has only a palliative role in the treatment of MTC [13]. Surgery remains the only standard treatment for patients with MTC: total thyroidectomy that is performed before MTC grows or spreads beyond the gland is currently the only curative therapy.Once MTC metastasizes, it has a tendency to spread to local and regional lymph nodes, and more distantly to lung, liver, and bone [8]. Although MTC is often widely metastatic, it tends to be a slow growing tumor. Patients with metastatic disease continue to have 5 and 10 year survival rates of 80% and 70%, respectively [14]. However, and despite its slow growth, the average survival for MTC is lower than that for other more common types of thyroid cancer, such as papillary and follicular carcinoma which have a 90% to 94% 5-year survival rate, respectively [15]. Decreased survival in MTC can be correlated with the stage of diagnos...

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Section: Ongoing Challenges and Unmet Needsmentioning

confidence: 99%

RET oncogene in MEN2, MEN2B, MTC and other forms of thyroid cancer

Lodish¹,

Stratakis²

2008

Expert Review of Anticancer Therapy

105

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“…[8][9][10] In an attempt to overcome imatinib resistance, 2 nd -generation tyrosine kinase inhibitors were developed, including dasatinib, nilotinib, bosutinib, and ponatinib. [11][12][13][14] However, the costs of 2nd-generation tyrosine kinase inhibitors may be prohibitive, particularly in emerging regions such as the Asia-Pacific countries, and new, lower cost alternatives are necessary. [15][16][17][18] Radotinib (Supect™; C27H21F3N8OHCl, 4-Methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyrazin-2-yl-pyrimidin-2-ylamino)-benzamide hydrochloride; IL-YANG Pharm.…”

Section: Introductionmentioning

confidence: 99%

Efficacy and safety of radotinib in chronic phase chronic myeloid leukemia patients with resistance or intolerance to BCR-ABL1 tyrosine kinase inhibitors

et al. 2014

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“…4). One study demonstrated that even a two-fold increase in fusion transcript levels was tightly associated with the presence of mutations [53]; current recommendations suggest that a 5-to 10-fold increase in levels might prompt mutation testing [39]. A variety of different technologies are available to identify and quantify KD mutations and include [herein listed from least sensitive (15-25%) to most sensitive (0.01%)]: direct sequencing, subcloning and sequencing, denaturing high-performance liquid chromatography (DHPLC), pyrosequencing, and allele-specific oligonucleotide PCR.…”

Section: Imatinib Resistancementioning

confidence: 99%

“…Primary resistance is defined as the failure to achieve an initial response to therapy and is seen in only 5% of newly diagnosed patients in chronic phase CML [39]. Mechanistically, primary resistance is typically BCR-ABL1 independent [40].…”

Section: Imatinib Resistancementioning

confidence: 99%

“…This is defined as a loss of a documented hematologic or cytogenetic response, the latter often seen concurrently with an increase in fusion transcript levels. Secondary resistance appears to increase by 1-4% each year in patients in early CP [39] but develops more frequently in AP and BP [43,44]. The proportion of patients developing resistance is also higher in patients who have received prior interferonalpha therapy [45].…”

Section: Imatinib Resistancementioning

confidence: 99%

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Molecular diagnosis and monitoring in the clinical management of patients with chronic myelogenous leukemia treated with tyrosine kinase inhibitors

Vergilio

Bagg

2007

American J Hematol

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The well-established molecular pathogenesis of chronic myelogenous leukemia (CML) and its consequences for laboratory testing and clinical management illustrate a classic paradigm for the importance of molecular diagnostics in targeted drug therapy. The success of the tyrosine kinase inhibitor (TKI), imatinib, as the currently recommended first-line treatment of early chronic phase CML has both fueled the need for timely and reproducible molecular testing of the BCR-ABL1 fusion transcript in diagnosis and monitoring as well as necessitated the detection of kinase domain mutations that confer resistance to this agent. As, ongoing research continues to refine guidelines for monitoring residual disease in patients undergoing TKI therapy, an understanding of molecular technologies and their interpretation is critical. This review summarizes the molecular strategies that are currently employed in the initial diagnosis and subsequent management of CML patients maintained on TKI therapy. Am. J. Hematol. 83:296-302, 2008. V V C 2007 Wiley-Liss, Inc. Molecular Basis of CMLChronic myelogenous leukemia (CML), which comprises 15-20% of all adult leukemias, is the first human neoplasm to be associated with a single, specific, acquired oncogenic mutation, namely the fusion of ABL1 (chromosome 9) and BCR (chromosome 22) genes. CML is a clonal stem cell disease that results in expanding myelopoiesis, with a natural history characterized by three phases: chronic (CP), accelerated (AP), and blast phase (BP); BP is synonymous with blast crisis. Classically, the chronic (or stable) phase lasts for three to five years, during which myeloid hyperplasia results in circulating granulocytes in all stages of maturation with associated basophilia. While the typical triphasic nature of CML is well accepted [1], there is significant variability in the published literature as to the specific criteria for diagnosing AP and, to some degree, BP. Nonetheless, in AP, myeloid elements begin to lose the ability to differentiate with an inevitable evolution to BP that is characterized by acute leukemia of predominantly myeloid (70%), but not uncommonly lymphoid (30%), phenotype [2].The acquired cytogenetic abnormality that is essentially diagnostic of CML in the appropriate hematologic context is the Philadelphia chromosome (Ph) [3], a truncated chromosome 22 resulting from a reciprocal t(9;22)(q34;q11) translocation. This translocation, which fuses the BCR and ABL1 genes [4], has been identified as the initial transforming event in CML pathogenesis, although some data suggest that it may be preceded by clonal hematopoiesis [5]. The BCR gene encodes a cytoplasmic protein that is thought to act as a tumor suppressor in the Wnt signaling pathway [6] as well as function in the cellular trafficking of growth factor receptors [7]. ABL1, which localizes to the nucleus, plasma membrane, and cytoskeleton, encodes a nonreceptor tyrosine kinase involved in normal hematopoiesis. The resultant chimeric fusion protein, located in the cytosol, has constitutively ...

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Defining and Managing Imatinib Resistance

Cited by 71 publications

References 42 publications

RET oncogene in MEN2, MEN2B, MTC and other forms of thyroid cancer

RET oncogene in MEN2, MEN2B, MTC and other forms of thyroid cancer

Efficacy and safety of radotinib in chronic phase chronic myeloid leukemia patients with resistance or intolerance to BCR-ABL1 tyrosine kinase inhibitors

Molecular diagnosis and monitoring in the clinical management of patients with chronic myelogenous leukemia treated with tyrosine kinase inhibitors

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