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Cancer remains a leading cause of death in the developed world. Survival rates for patients with common cancers detected at an advanced stage are still low. Only about 10% of patients with metastatic colon cancer and about 5% of patients with pancreatic cancer survive for more than 5 years. Cancer therapies are still largely chosen on the basis of diagnostic categories, and all patients of a particular tumor type and stage of disease receive the same treatment. Biological heterogeneity among patients has long been recognized, but the significance of these differences with respect to the course of disease and drug responsiveness is just starting to be understood. In addition, the limited repertoire of available drugs has made it difficult to exploit these differences for different treatment strategies.

Tumorigenesis is a multistep process whereby an individual cell acquires a series of mutant gene products. These genetic changes culminate in proliferation, growth, blocked differentiation, induction of angiogenesis, tissue invasion, and loss of genomic stability. Given the genetic complexity of tumorigenesis, it is perhaps surprising that there are circumstances in which cancer can be reversed through the repair or inactivation of individual mutant genes. However, recent experiments in transgenic mouse models and clinical results with new pharmacological agents demonstrate that cancer can be treated through the targeted repair and/or inactivation of mutant proteins. Hence, cancers appear to be dependent upon particular oncogenes to maintain their neoplastic properties, thus exhibiting the phenomenon of “oncogene addiction.”

Cancer is the second leading cause of death in the western world and is an increasing health problem in the developing world. Overall survival of patients with advanced cancer is poor. Until recently, surgery, chemotherapy, radiotherapy and endocrine therapy have been the mainstay in the treatment of cancer patients. This has improved outcomes in certain tumour types but treatment-related toxicity and emergence of drug resistance have been the major cause of morbidity and mortality. This need to improve outcomes has stimulated intense scientific research in recent years. Several novel drug targets have been identified. Amongst these, tyrosine kinases have emerged as the new promising anti-cancer drug target. Inhibitors of BCR-ABL, EGFR and VEGFR tyrosine kinases have now been licenced for use in cancers. In this chapter, we will discuss how this has been achieved in recent years.

Tyrosine kinases are a large and diverse family of proteins found only in metazoans. The ERBB family, which encompasses subgroup I of the receptor tyrosine kinase (RTK) superfamily, has four members: epidermal growth factor receptor (EGFR)/ErbB1, ErbB2, ErbB3, and ErbB4. ERBB RTKs contain an extracellular domain that binds peptide ligands; they span the membrane once and have an intracellular portion with protein tyrosine kinase activity (Fig. 4.1). Ligand binding induces the formation of receptor dimers, and as a consequence the intrinsic kinase of the receptor is activated and transfers a phosphate group from the bound ATP to specific tyrosine side chains on the receptor proteins and on intracellular signaling proteins that bind the active RTKs. Subsequently, multiple signaling pathways become activated. The ERBB receptor/ligand family has been investigated in depth for many years, and comprehensive signaling maps describing the links between the plasma membrane receptors, the cytoplasmic signaling pathways, and the nucleus are available ( Oda 2005 ).

Insulin-like growth factor (IGF) signaling plays a critical role in the growth and differentiation of many tissues, particularly in prenatal growth and puberty. The IGF axis is also implicated in various pathophysiological conditions, and is believed to play a crucial role in tumorigenesis ( Pollak et al. 2004 ).

Transforming growth factor—β (TGF—β) plays an important physiologic role in the regulation of cell proliferation, motility, and apoptosis as well as extracellular matrix (ECM) production. It therefore modulates physiologic functions such as embryonic development, wound healing, vasculogenesis and angiogenesis, as well as immune surveillance. Moreover, TGF—β has been associated with a wide variety of diseases: atherosclerosis; fibrotic diseases of the lung, kidney, and liver; Alzheimer disease; developmental defects; hereditary hemorrhagic teleangiectasia; as well as both solid tumors and hematologic malignancies. Importantly, TGF—β signaling pathways mediate both early-stage tumor- suppressing, as well as late-stage tumor-promoting, effects. In addition, TGF—β can synergize with oncogenes in transformation and tumor progression. Recent therapeutic approaches in cancer target TGF—β signaling, either alone or in combination with conventional or novel targeted therapy, to improve patient outcome.

Human cancer expression profiling studies highlight the important variability in gene expression patterns and signaling pathways activated within tumors of a homogenous pathological group. These observations support the need for marker and molecular signature identification to adapt appropriate treatments to the patient. Increasing evidence indicates that the mammalian target of rapamycin [mTOR; also named rapamycin-associated protein (FRAP) or rapamycin and FKBP12 target (RAFT)] signaling pathway is hyperactive in a number of cancers, suggesting that this pathway may represent an attractive target for cancer therapy. mTOR is a highly conserved, 290-kDa serine-threonine protein kinase that belongs to the phosphoinositide kinase-related kinase (PIKK) family comprising also ataxia-telangiectasia (ATM), ATM and Rad3-related protein kinase (ATR) and DNA-dependent protein kinase (DNA-PK) ( Abraham 2004 ).

The Ras GTPase proteins and their down-stream effectors regulate specific intracellular signalling pathways involved in numerous biological processes. Their actions directly influence progression through the cell cycle and the delicate balance of pro- and anti-apoptotic factors. The variety of functions controlled by Ras, and the emerging evidence indicating that aberrations in Ras as well as at multiple points in downstream signalling pathways contribute to tumourigenesis, suggest that Ras signal transduction mechanisms have significant potential as anti-cancer therapeutic targets.

The molecular characterization of key events associated with tumor initiation and progression has led to the identification of cellular signaling pathways that contribute not only to normal cell functioning but also to the overall phenotype associated with cancer. One such example is the Ras-regulated kinase pathway. This signaling module, comprising Raf, mitogen-activated protein kinase kinase (MEK), and extracellular signal-regulated kinase (ERK), plays a central role in regulating a broad range of cellular events. In response to a diverse group of extracellular stimuli including growth factors, cytokines, and protooncogenes, activation of this pathway results in alterations in cell proliferation, differentiation, and survival. It is therefore not surprising that this pathway has been found to be upregulated in a large percentage of human tumors. While contributing to the uncontrolled growth and enhanced survival of tumor cells, the Ras-MAP kinase pathway also plays a key role in their metastatic spread by regulating cell motility and invasion.

In the past decade, we have gained substantial insight into various signal transduction and molecular pathways regulating cancer cells. Moreover, we have recently been able to develop specific targeted therapies instead of classic chemotherapeutics that attempt to essentially provide more toxicity to the tumor than the normal cell. As a result, we have been able to decrease adverse side effects, thus improving the quality of life of cancer patients.