title: Targeted cancer therapy: what if the driver is just a messenger?
abstract: "Shoot the driver" is the paradigm of targeted cancer therapy. However, resistance to targeted inhibitors of signaling pathways is a major problem. In part the redundancy of signaling networks can bypass targeted inhibitors and thereby reduce their biological effect. In this case the driver turns out to be one of several potential messengers and is easily replaced. Cocktails of multiple targeted inhibitors are an obvious solution. This is limited, however, by the lack of potent inhibitors and may also produce increased toxicity. Therefore we explored the direct blockade of a key biological activity downstream from multiple converging oncogenic signals. Specifically, several oncogenic signaling pathways including AKT, MAPK and PIM kinase signals converge on the activation of cap-dependent translation. In cancer cells, aberrant activation of cap-dependent translation favors the increased expression of short-lived oncoproteins like c-MYC, MCL1, CYCLIN D1 and the PIM kinases. Intriguingly, cancer cells are especially sensitive to even temporary reductions in these proteins. We will discuss our findings concerning translational inhibitor therapy in cancer.
authors: Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA. schatzj@mskcc.org
authors: Jonathan H
authors: JH
authors: Schatz
authors: Hans-Guido
authors: HG
authors: Wendel
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000037:antagonists & inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051573:Proto-Oncogene Proteins c-pim-1 / Q000378:metabolism*; D011724:Pyridazines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D014315:Triterpenes / Q000494:pharmacology* / Q000627:therapeutic use; D001572:Benzofurans
chemical_list: D000970:Antineoplastic Agents; D007093:Imidazoles; D020929:Mitogen-Activated Protein Kinase Kinases; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D051573:Proto-Oncogene Proteins c-pim-1; D011724:Pyridazines; D014315:Triterpenes; C545188:SGI 1776; C489897:silvestrol; D001572:Benzofurans; C406031:proto-oncogene proteins pim