homoharringtonine and bosutinib

Chronic myeloid leukemia (CML) is driven by the BCR-ABL1 fusion protein, formed by a translocation between chromosomes 9 and 22 that creates the Philadelphia chromosome. The BCR-ABL1 fusion protein is an optimal target for tyrosine kinase inhibitors (TKIs) that aim for the adenosine triphosphate (ATP) binding site of ABL1. While these drugs have greatly improved the prognosis for CML, many patients ultimately fail treatment, some requiring multiple lines of TKI therapy. Mutations can occur in the ATP binding site of ABL1, causing resistance by preventing the binding of many of these drugs and leaving patients with limited treatment options. The approved TKIs are also associated with adverse effects that may lead to treatment discontinuation in some patients. Efficacy decreases with each progressive line of therapy; data suggest little clinical benefit of treatment with a third-line (3L), second-generation tyrosine kinase inhibitor (2GTKI) after failure of a first-generation TKI and a 2GTKI. Novel treatment options are needed for the patient population that requires treatment in the 3L setting and beyond. This review highlights the need for clear guidelines and new therapies for patients requiring 3L treatment and beyond.

Topics: Aniline Compounds; Animals; Antineoplastic Agents; Clinical Trials as Topic; Fusion Proteins, bcr-abl; Homoharringtonine; Humans; Imidazoles; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Molecular Targeted Therapy; Niacinamide; Nitriles; Protein Kinase Inhibitors; Pyrazoles; Pyridazines; Quinolines

The advent of targeted oncolytic agents has created a revolution in the treatment of malignancies. Perhaps best exemplified in myeloproliferative neoplasms (MPN), the tyrosine kinase inhibitors, including inhibitors of BCR-ABL tyrosine kinase and JAK2, have dramatically changed outcomes in persons with MPN. However, clinically relevant dosing of these adenosine triphosphate-mimetic agents in humans leads to inhibition of numerous tyrosine kinases beyond those touted by drug manufacturers and studied in landmark clinical trials. These so-called off-target effects have been linked to both clinical efficacy and toxicity. Rational drug development and serendipitous discovery of drug molecules allows the clinician to select targeted oncolytic agents to treat a specific clinical diagnosis and/or avoid exacerbation of concomitant disease states due to effects upon signaling pathways. Understanding the off-target binding and effects upon signaling pathway of the agents approved for the treatment of MPN will empower the clinician to adroitly select pharmacotherapy, predict toxicities, and utilize these agents in clinical practice for indications beyond MPN.

Topics: Aniline Compounds; Antineoplastic Agents; Carbazoles; Dasatinib; Drug-Related Side Effects and Adverse Reactions; Eosinophilia; Furans; Fusion Proteins, bcr-abl; Gastrointestinal Stromal Tumors; Graft vs Host Disease; Harringtonines; Homoharringtonine; Humans; Hypertension, Pulmonary; Imatinib Mesylate; Imidazoles; Janus Kinase 2; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Mastocytosis; Myeloproliferative Disorders; Nitriles; Polycythemia Vera; Primary Myelofibrosis; Protein Kinase Inhibitors; Pulmonary Fibrosis; Pyrazoles; Pyridazines; Pyrimidines; Quinolines; Scleroderma, Systemic; Smallpox; Thrombocythemia, Essential; Tuberculosis, Multidrug-Resistant

The emergence of resistance to imatinib has become a significant problem despite the remarkable clinical results achieved with this tyrosine kinase inhibitor in the treatment of chronic myeloid leukaemia. The most common cause of imatinib resistance is the selection of leukemic clones with point mutations in the Abl kinase domain. These mutations lead to amino acid substitutions and prevent the appropriate binding of imatinib. Genomic amplification of BCR-ABL, modulation of drug efflux or influx transporters, and Bcr-Abl-independent mechanisms also play important roles in the development of resistance. Persistent disease is another therapeutic challenge and may in part, be due to the inability of imatinib to eradicate primitive stem cell progenitors. A multitude of novel agents have been developed and have shown in vitro and in vivo efficacy in overcoming imatinib resistance. In this review, we will discuss the current status of the ATP-competitive and non-ATP-competitive Bcr-Abl tyrosine kinase inhibitors. We will also describe inhibitors acting on targets found in signaling pathways downstream of Bcr-Abl, such as the Ras-Raf-mitogen-activated protein kinase and phosphatidylinositol-3 kinase-Akt-mammalian target of rapamycin pathways, and targets without established links with Bcr-Abl.

Topics: Aniline Compounds; Antineoplastic Agents; Arsenic Trioxide; Arsenicals; Benzamides; Clinical Trials as Topic; Dasatinib; Drug Resistance, Neoplasm; Enzyme Inhibitors; Fusion Proteins, bcr-abl; Gene Amplification; Harringtonines; Histone Deacetylase Inhibitors; Homoharringtonine; Humans; Imatinib Mesylate; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Nitriles; Oxides; Piperazines; Protein-Tyrosine Kinases; Pyrimidines; Quinolines; Thiazoles