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A number of successful systemic therapies are available for the treatment of disseminated cancers. However, tumor response is often transient, and therapy frequently fails due to emergence of resistant populations. The latter reflects the temporal and spatial heterogeneity of the tumor microenvironment as well as the evolutionary capacity of cancer phenotypes to adapt to therapeutic perturbations. Resistance to either chemotherapy and targeted agents limits the effectiveness of current cancer therapies, including those used to treat metastatic colorectal cancer (mCRC) which is one of the leading causes of cancer-related death worldwide. Resistance to therapeutic drugs can be already present at diagnosis or it can develop after treatment. These two forms of resistance are respectively called intrinsic and acquired. The identification of mechanisms of drug resistance may highlight new biomarkers useful to predict the clinical outcome or the likely responsiveness to pharmacological treatment of those metastatic CRC patients who cannot benefit from current therapeutic regimen. Moreover, the recognition of panels of biomarkers may suggest new strategies to overcome resistance by rational drug design and combination treatment. In this review, we describe molecular mechanisms of resistance to chemotherapies and targeted agents that may be relevant to colorectal cancer and the possible strategies to overcome the resistance.

The prognosis of patients with pancreatic cancer is extremely poor, and current systemic therapies provide marginal survival benefits for treated patients. The era of targeted therapies has offered a new avenue to search for potentially more effective strategies. Epidermal growth factor receptor (EGFR) is a member of the erbB/human epidermal growth factor receptor family of tyrosine kinases, which includes erbB2/HER2, erbB3/HER3 and erbB4/HER4. Epidermal growth factor receptor overexpression may be detected in up to 90 of pancreatic tumors. Two pharmacologic approaches have been successfully used to inhibit epidermal growth factor receptor function in cancer treatment: neutralizing monoclonal antibodies and small molecule tyrosine inhibitors. The randomized trials studying the addition of EGFR targeted agents to gemcitabine compared with gemcitabine alone have been disappointing, although results with the EGFR tyrosine kinase inhibitor erlotinib were statistically significant but clinically of marginal benefit. In this article, we review the epidermal growth factor receptor signaling network in pancreatic cancer, the strategies to increase the effectiveness of epidermal growth factor receptor inhibitors, and the clinical trials of these inhibitors in pancreatic cancer.

Over the last decade, the concept of targeted biological therapy for the treatment of cancer has emerged. However, a better understanding of these targets and their role in tumor cells and in the surrounding stromal cells is required. Two interesting biological targets are the epidermal growth factor receptor (EGFR) and the vascular endothelia growth factor (VEGF) and its receptors. A number of agents that target these pathways have been described. Many of these are currently in clinical trials and a few have recently been approved by the regulatory authorities in USA and in the European Union. The molecular pathways involved in the proliferation of cancer cells and in tumor-related angiogenesis are very complex and the interference with only a single step of these pathways may often reveal an insufficient therapeutic approach. Moreover, cancer cells have an inherent ability to harness different growth factor signaling pathways for growth advantage and cell survival, a process that may even be facilitated by the use of selective targeted agents. Because of these escape mechanisms, monotherapy with selective targeted agents is unlikely to be a fully effective cancer treatment. For these reasons, targeting different pathways is an attractive and effective therapeutic strategy with a strong rationale for investigating this approach in the clinic. This review focuses on the preclinical rationale of combining targeted agents such as EGFR and VEGF inhibitors in the treatment of cancer and on the clinical trials that have emerged from these studies.

Epidermal growth factor receptor (EGFR) inhibitors are in clinical development in cancer treatment. Preclinical studies have shown potential antitumor efficacy of these agents in combination with chemotherapy or with radiotherapy. However, controversial results have been obtained in different clinical trials.

The currently available treatment of cancer patients is based on the use of cytotoxic drugs and/or of ionizing radiations, which have potent antitumor activity, but also cause clinically relevant side effects, since they affect cellular targets that are common to both cancer cells and normal proliferating cells. In the past 20 years, the discoveries on the molecular mechanisms of cancer development and progression have prompted the search for agents which are more selective for cancer cell molecular targets. The possibility of combining conventional cytotoxic drugs with novel agents that specifically interfere with key pathways controlling cancer cell survival, proliferation, invasion and/or metastatic spreading has generated a wide interest. This could be a promising therapeutic approach for several reasons. First, since the cellular targets for these agents and their mechanism(s) of action are different from those of cytotoxic drugs, it is possible for their combination with chemotherapy without cross-resistance. Second, alterations in the expression and/or the activity of genes that regulate mitogenic signals not only can directly cause perturbation of cell growth, but also may affect the sensitivity of cancer cells to conventional chemotherapy and radiotherapy. In this review, we will discuss the biologic bases of the combination of molecular targeted drugs with conventional medical cancer treatments and the available results of the first series of clinical trials in cancer patients.