Novel Strategies to Improve the Efficacy of Anticancer Agents in Human Colorectal Carcinoma
Figure 1: Inhibition of Epidermal Growth Factor Receptor 1 (EGFR1) by Anti-EGFR1 Antibodies in Colorectal Carcinoma Cells (A) and Vascular Endothelial Growth Factor Signalling Pathways by Bevacizumab in Endothelial Cells (B)
A. Cancer cells
Monoclonal antibodies against EGFR1 (i.e. cetuximab, panitumumab)
ErbB3
EGFR or ErbB2
VEGFR Cell membrane
TKI TKI SOS P13K RAS MAPK AKT AKT MAPK
Tumour cell proliferation Differentiation Survival
Migration
SRC Cell membrane
P P P
B. Endothelial cells
Monoclonal antibodies against VEGF (i.e. bevacizumab)
Proliferation Differentiation
Membrane degradation Survival
Migration
EGFR1 = epidermal growth factor receptor; MAPK = mitogen-activated protein kinase; P13K = phosphatidylinositol-3-kinase; RAS = Kirsten rat sarcoma viral oncogene homologue; SOS = son of sevenless homologue; VEGFR = vascular endothelial growth factor receptor.
The combination of cetuximab or panitumumab with IRI- or l-OHP- based chemotherapy was proved to increase response rate and prolong progression-free survival in the first-line treatment of patients with metastatic CRC.27
Furthermore, the inhibition of the EGFR1
pathway results in the restoration of the sensitivity to IRI or l-OHP by restoring mechanisms of chemoresistance.7,27
Recently, several groups have shown that activating mutations in the K-RAS protein, which partially transduces the activation signal from EGFR1, abrogates the therapeutic effect of anti-EGFR1 therapy.28–30 These results have restricted the use of anti-EGFR1 to the set of patients with wild-type K-RAS tumours. However, selection of patients on the basis of K-RAS status is not perfect. While the test for non- response is highly specific (nearly 95% of patients with somatic mutations of K-RAS fail to respond to anti-EGFR1 therapy), 40–60% of patients with wild-type K-RAS fail to respond to the treatment.31
This
suggests that there are other important molecular determinants of response that have yet to be determined. The identification of these predictive biomarkers of the response to anti-EGFR1 agents represents a major strategy for tailoring treatments on the molecular profile of each tumour in order to improve patient outcomes and reduce toxicities.
Angiogenesis, the formation of new blood vessels from pre-existing vessels, allows tumours to absorb nutrients and oxygen for their further growth, and helps cancer cells to access the systemic circulation and establish metastases. The switch to an angiogenic
EUROPEAN ONCOLOGY
phenotype is caused by an increased production of pro-angiogenic factors, including VEGF and basic and acidic fibroblast growth factor (FGF), and a decrease in angiogenic inhibitors.32
VEGF is a specific
mitogen for the endothelial cell and acts as a survival factor through the inhibition of apoptosis, also playing an important role in mobilising endothelial cell precursors to sites of angiogenesis (see Figure 1B).33 VEGF is upregulated in most human tumours, including CRC.33 Bevacizumab is an anti-VEGF humanised monoclonal antibody and is the most advanced agent of its class in clinical development. Several studies have examined bevacizumab in combination with chemotherapy in first- and second-line settings in patients with metastatic CRC. Indeed, the addition of bevacizumab to FU/l-OHP- or FU/IRI-based chemotherapy results in a significantly longer survival time, greater overall response rate, longer duration of response and longer progression-free survival in metastatic CRC.34,35
It is noteworthy
that, at present, there are no molecular determinants predictive of the response to anti-angiogenic therapies.
Drug Resistance in Colorectal Carcinoma
Drug resistance is a multifactorial phenomenon involving multiple inter-related or independent pathways, including changes in cellular responses, such as increased cell ability to repair DNA damage or tolerate stress conditions and acquiring mechanisms for escaping apoptosis.36
cytoprotective effects and have been characterised as molecular chaperones, proteins with the property of modifying the structures and interactions of other proteins.37
The levels of HSPs are elevated in
57
Angiogenesis
Most heat shock proteins (HSPs) have strong
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