Seeking the causes and solutions to imatinib-resistance in chronic myeloid leukemia

Abstract

Although only 5000 new cases of chronic myeloid leukemia (CML) were seen in the United States in 2009, this neoplasm continues to make scientific headlines year-after-year. Advances in understanding the molecular pathogenesis coupled with exciting developments in both drug design and development, targeting the initiating tyrosine kinase, have kept CML in the scientific limelight for more than a decade. Indeed, imatinib, a small-molecule inhibitor of the leukemia-initiating Bcr-Abl tyrosine kinase, has quickly become the therapeutic standard for newly diagnosed chronic phase-CML (CP-CML) patients. Yet, nearly one-third of patients will still have an inferior response to imatinib, either failing to respond to primary therapy or demonstrating progression after an initial response. Significant efforts geared toward understanding the molecular mechanisms of imatinib resistance have yielded valuable insights into the cellular biology of drug trafficking, enzyme structure and function, and the rational design of novel small molecule enzyme inhibitors. Indeed, new classes of kinase inhibitors have recently been investigated in imatinibresistant CML. Understanding the pathogenesis of tyrosine kinase inhibitor resistance and the molecular rationale for the development of second and now third generation therapies for patients with CML will be keys to further disease control over the next 10 years.

Therapeutic Targeting of the Cancer-Specific Cell Surface Biomarker nfP2X7

“…Additional confirmations, many very recently, of the up-regulation of the receptor in cancer tissue have been obtained for pancreatic [43], lung [44], skin [45][46][47], brain [48,49], renal [38], prostate [50], thyroid [51], bone [52] and both ALL and AML [53,54].…”

“…The benefits are specific targeting, lower doses needed to target the tumour, and no unwanted side effects from off-target binding. That the target is highly conserved across species indicates that mutational drift in the target, as a result of therapeutic intervention, as is the case with easily mutable targets such as BCR-ABL, c-KIT and PDGFRA tyrosine kinases [53,54], is less likely to occur.…”

Treatment of Chronic Myeloid Leukaemia: Current Practice and Future Prospects

“…Bosutinib is currently undergoing frontline testing against imatinib with promising results. This third generation TKI may shortly win FDA approval for initial therapy of CML (Bixby & Talpaz, 2011). INNO-406 is an orally bioavailable dual Abl/Lyn kinase inhibitor which is up to 50 times more potent than imatinib against Bcr-Abl.…”

Regional Evaluation of Tolerability and Efficacy of Imatinib Mesylate in Patients with Chronic Phase CML in Mashhad (Iran, Southwest Asia)

“…Patients considered imatinib-resistant with failing to have achieved a complete hematological response (CHR) by 3 months [6]. In most patients molecular response were assessed by nested RT/PCR Abl-Bcr in peripheral blood every 6 months.…”