r malignant behaviour is usually driven by the accumulation of several genetic and epigenetic aberrations. Emerging evidence indeed indicates that clinically successful new therapeutic strategies will most likely rely on the selection of patients whose tumours harbour genetic aberrations that render them addicted to the constitutive activation of a certain AB1010 c-Kit inhibitor pathway, as well as on the mechanism based manipulation of multiple, cross talking pathways involved in growth and survival control. Moreover, the therapeutic inactivation of an essential protein creates selective pressures for tumour cells to evolve mechanisms of resistance, in a manner similar to the extensively studied emergence of resistance in microorganisms after exposure to antimicrobial agents.
In this review, we will focus on the molecular mechanisms of sensitivity/resistance to agents targeted at EGFR and mitogen activated protein kinase, with particular emphasis on EGFR/MAPK inhibition based combination strategies, designed PXD101 414864-00-9 to achieve synergistic antitumour activity and to overcome resistance to the single agent. Tortora et al. Page 2 Drug Resist Updat. Author manuscript, available in PMC 2008 September 23. NIH PA Author Manuscript NIH PA Author Manuscript NIH PA Author Manuscript 2. Mechanisms of resistance to EGFR tyrosine kinase inhibitors Resistance to targeted agents may occur by mechanisms similar to cytotoxic agent resistance such as inactivating metabolism, poor absorption, reduced drug availability or defective immune system mediated functions.
An example is the acquired resistance to imatinib as a result of increased plasma activity of 1 acid glycoprotein, an acute phase reactant which binds the drug and reduces its availability to neutralize BCR ABL kinase activity in the tumour. Most relevant causes of targeted drug resistance are: 1. specific mutations or loss of the target, 2. activation of alternative TK receptors that bypass the pathway targeted by the specific agent, 3. independent or constitutive activation of intracellular molecular effectors downstream to the target protein, 4. activation of tumour induced angiogenesis. 5. constitutive EGFR activity. All these mechanisms have been described as important determinants of the resistance to inhibitors of ErbB/HER family receptors, particularly EGFR and HER2.
Therefore, the mechanisms of resistance to EGFR inhibitors may be considered a general paradigm for other molecularly targeted drugs. 2.1. Gene mutations and loss of the target EGFR mutations were described in various human malignancies including breast, gliomas, prostate, lung and ovarian cancer several years ago. Among them, the most extensively characterized is the EGFR variant III, containing an in frame deletion from exons 2 through 7 in the extracellular domain of EGFR, that prevents the mutated receptor from binding ligands and results in a constitutive EGFR activation. This mutation is the most frequently expressed EGFR genetic alteration in some cancers, such as glioblastomas, but it is also reported in breast cancer. GBM cell lines expressing this mutated variant EGFRvIII are relatively resistant to gefitinib, higher doses and longer exposure to this agent are necessary to significantly decrease EGFRvIII phosphorylation. The protective activity of EGFRvIII may be due to phosphorylation of AKT, which gefitinib is unable to prevent in cells expressing EGFRvIII. In the past two years several studies have correlated EGFR mutations with sensitivity