Overcoming resistance to molecularly targeted anticancer therapies: rational drug combinations based on EGFR and MAPK inhibition for solid tumours and haematologic malignancies

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dc.contributor.authorTortora, Giampaoloen_US
dc.contributor.authorBianco, Robertoen_US
dc.contributor.authorDaniele, Gennaroen_US
dc.contributor.authorCiardiello, Fortunatoen_US
dc.contributor.authorMcCubrey, James A.en_US
dc.contributor.authorRicciardi, Maria Rosariaen_US
dc.contributor.authorCiuffreda, Ludovicaen_US
dc.contributor.authorCognetti, Francescoen_US
dc.contributor.authorTafuri, Agostinoen_US
dc.contributor.authorMilella, Micheleen_US
dc.date.accessioned2011-01-28T19:47:47Zen_US
dc.date.accessioned2011-05-17T01:39:59Z
dc.date.available2011-01-28T19:47:47Zen_US
dc.date.available2011-05-17T01:39:59Z
dc.date.issued2007-06en_US
dc.description.abstractAccumulating evidence suggests that cancer can be envisioned as a "signaling disease", in which alterations in the cellular genome affect the expression and/or function of oncogenes and tumour suppressor genes. This ultimately disrupts the physiologic transmission of biochemical signals that normally regulate cell growth, differentiation and programmed cell death (apoptosis). From a clinical standpoint, signal transduction inhibition as a therapeutic strategy for human malignancies has recently achieved remarkable success. However, as additional drugs move forward into the clinical arena, intrinsic and acquired resistance to "targeted" agents becomes an issue for their clinical utility. One way to overcome resistance to targeted agents is to identify genetic and epigenetic aberrations underlying sensitivity/resistance, thus enabling the selection of patients that will most likely benefit from a specific therapy. Since resistance often ensues as a result of the concomitant activation of multiple, often overlapping, signaling pathways, another possibility is to interfere with multiple, cross-talking pathways involved in growth and survival control in a rational, mechanism-based, fashion. These concepts may be usefully applied, among others, to agents that target two major signal transduction pathways: the one initiated by epidermal growth factor receptor (EGFR) signaling and the one converging on mitogen-activated protein kinase (MAPK) activation. Here we review the molecular mechanisms of sensitivity/resistance to EGFR inhibitors, as well as the rationale for combining them with other targeted agents, in an attempt to overcome resistance. In the second part of the paper, we review MAPK-targeted agents, focusing on their therapeutic potential in hematologic malignancies, and examine the prospects for combinations of MAPK inhibitors with cytotoxic agents or other signal transduction-targeted agents to obtain synergistic anti-tumour effects. Originally published Drug Resistance Updates, Vol. 10, No. 3, June 2007en_US
dc.identifier.citationDrug Resistance Updates; 10:3 p. 81-100en_US
dc.identifier.pmidPMC2548422en_US
dc.identifier.urihttp://hdl.handle.net/10342/3136en_US
dc.language.isoen_USen_US
dc.publisherEast Carolina Universityen_US
dc.relation.urihttp://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WDK-4NNPCS2-1&_user=634873&_coverDate=06%2F30%2F2007&_rdoc=1&_fmt=high&_orig=search&_origin=search&_sort=d&_docanchor=&view=c&_acct=C000033758&_version=1&_urlVersion=0&_userid=634873&md5=53d571ce5823827e90bdf9954bd13ab1&searchtype=aen_US
dc.rightsAuthor notified of opt-out rights by Cammie Jenningsen_US
dc.subjectTargeted therapyen_US
dc.subjectDrug resistanceen_US
dc.subjectCombination therapyen_US
dc.subjectMolecular markersen_US
dc.subjectEGFRen_US
dc.subjectIGFR1en_US
dc.subjectMAPKen_US
dc.subjectMEK inhibitorsen_US
dc.subjectAMLen_US
dc.titleOvercoming resistance to molecularly targeted anticancer therapies: rational drug combinations based on EGFR and MAPK inhibition for solid tumours and haematologic malignanciesen_US
dc.typeArticleen_US

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