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

Giampaolo Tortora, Roberto Bianco, Gennaro Daniele, Fortunato Ciardiello, James A. McCubrey, Maria Rosaria Ricciardi, Ludovica Ciuffreda, Francesco Cognetti, Agostino Tafuri, Michele Milella

Research output: Contribution to journalArticle

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 haematologic 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.

Original languageEnglish
Pages (from-to)81-100
Number of pages20
JournalDrug Resistance Updates
Volume10
Issue number3
DOIs
Publication statusPublished - Jun 2007

Keywords

  • AML
  • Combination therapy
  • Drug resistance
  • EGFR
  • IGFR1
  • MAPK
  • MEK inhibitors
  • Molecular markers
  • Targeted therapy

ASJC Scopus subject areas

  • Cancer Research
  • Infectious Diseases
  • Oncology
  • Pharmaceutical Science

Fingerprint Dive into the research topics of 'Overcoming resistance to molecularly targeted anticancer therapies: Rational drug combinations based on EGFR and MAPK inhibition for solid tumours and haematologic malignancies'. Together they form a unique fingerprint.

  • Cite this