Overcoming resistance to molecularly targeted anticancer therapies: rational drug combinations based on EGFR and MAPK inhibition for solid tumours and haematologic malignancies
Author
Tortora, Giampaolo; Bianco, Roberto; Daniele, Gennaro; Ciardiello, Fortunato; McCubrey, James A.; Ricciardi, Maria Rosaria; Ciuffreda, Ludovica; Cognetti, Francesco; Tafuri, Agostino; Milella, Michele
Abstract
Accumulating 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 2007
Date
2007-06
Citation:
APA:
Tortora, Giampaolo, & Bianco, Roberto, & Daniele, Gennaro, & Ciardiello, Fortunato, & McCubrey, James A., & Ricciardi, Maria Rosaria, & Ciuffreda, Ludovica, & Cognetti, Francesco, & Tafuri, Agostino, & Milella, Michele. (June 2007).
Overcoming resistance to molecularly targeted anticancer therapies: rational drug combinations based on EGFR and MAPK inhibition for solid tumours and haematologic malignancies.
Drug Resistance Updates,
10(3),
81-
100. Retrieved from
http://hdl.handle.net/10342/3136
MLA:
Tortora, Giampaolo, and Bianco, Roberto, and Daniele, Gennaro, and Ciardiello, Fortunato, and McCubrey, James A., and Ricciardi, Maria Rosaria, and Ciuffreda, Ludovica, and Cognetti, Francesco, and Tafuri, Agostino, and Milella, Michele.
"Overcoming resistance to molecularly targeted anticancer therapies: rational drug combinations based on EGFR and MAPK inhibition for solid tumours and haematologic malignancies". Drug Resistance Updates.
10:3. (81-100),
June 2007.
September 26, 2023.
http://hdl.handle.net/10342/3136.
Chicago:
Tortora, Giampaolo and Bianco, Roberto and Daniele, Gennaro and Ciardiello, Fortunato and McCubrey, James A. and Ricciardi, Maria Rosaria and Ciuffreda, Ludovica and Cognetti, Francesco and Tafuri, Agostino and Milella, Michele,
"Overcoming resistance to molecularly targeted anticancer therapies: rational drug combinations based on EGFR and MAPK inhibition for solid tumours and haematologic malignancies," Drug Resistance Updates 10, no.
3 (June 2007),
http://hdl.handle.net/10342/3136 (accessed
September 26, 2023).
AMA:
Tortora, Giampaolo, Bianco, Roberto, Daniele, Gennaro, Ciardiello, Fortunato, McCubrey, James A., Ricciardi, Maria Rosaria, Ciuffreda, Ludovica, Cognetti, Francesco, Tafuri, Agostino, Milella, Michele.
Overcoming resistance to molecularly targeted anticancer therapies: rational drug combinations based on EGFR and MAPK inhibition for solid tumours and haematologic malignancies. Drug Resistance Updates.
June 2007;
10(3):
81-100.
http://hdl.handle.net/10342/3136. Accessed
September 26, 2023.
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Publisher
East Carolina University