homoharringtonine and Gastrointestinal-Stromal-Tumors

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

Although KIT-mutant GISTs can be effectively treated with tyrosine kinase inhibitors (TKIs), many patients develop resistance to imatinib mesylate (IM) as well as the FDA-approved later-line agents sunitinib, regorafenib and ripretinib. Resistance mechanisms mainly involve secondary mutations in the KIT receptor tyrosine kinase gene indicating continued dependency on the KIT signaling pathway. The fact that the type of secondary mutation confers either sensitivity or resistance towards TKIs and the notion that secondary mutations exhibit intra- and intertumoral heterogeneity complicates the optimal choice of treatment in the imatinib-resistant setting. Therefore, new strategies that target KIT independently of its underlying mutations are urgently needed. Homoharringtonine (HHT) is a first-in-class inhibitor of protein biosynthesis and is FDA-approved for the treatment of chronic myeloid leukemia (CML) that is resistant to at least two TKIs. HHT has also shown activity in KIT-mutant mastocytosis models, which are intrinsically resistant to imatinib and most other TKIs. We hypothesized that HHT could be effective in GIST through downregulation of KIT expression and subsequent decrease of KIT activation and downstream signaling. Testing several GIST cell line models, HHT led to a significant reduction in nascent protein synthesis and was highly effective in the nanomolar range in IM-sensitive and IM-resistant GIST cell lines. HHT treatment resulted in a rapid and complete abolishment of KIT expression and activation, while KIT mRNA levels were minimally affected. The response to HHT involved induction of apoptosis as well as cell cycle arrest. The antitumor activity of HHT was confirmed in a GIST xenograft model. Taken together, inhibition of protein biosynthesis is a promising strategy to overcome TKI resistance in GIST.

Topics: Antineoplastic Agents; Drug Resistance, Neoplasm; Gastrointestinal Neoplasms; Gastrointestinal Stromal Tumors; Homoharringtonine; Humans; Imatinib Mesylate; Mutation; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-kit