Efforts of cancer research have yielded sig-nificant advance in our understanding on the complexity of cancer during the past several decades. It is generally accepted that cancer development is a multi-step and multigenic event (Hahn and Weinberg, 2002). The hallmarks of cancer comprise a series of genetic and epigenetic gain- and loss-of-functions of oncogenes and tumor suppressor genes, respectively, that render cancer cells capable of unrestricted replication potential, resistance to pro-apoptotic stimuli, sustained angiogenesis, self-sufficiency in growth signals, insensi-tivity of growth suppressor signals, evasion of immune surveillance, energy metabolism reprogramming, and acquisition of tumor-promoting inflammation (Hanahan and Weinberg, 2011). With the explosion of knowledge on genes and molecular path-ways that govern those cancer hallmarks, mechanism-based target-specific therapies have been developed. The rapidly emerging role of targeted therapies may be considered one of the most remarkable developments in the field of cancer research and therapeu-tics over the past several decades.Most of the target-specific drugs have hitherto been designed to cripple proteins or molecular pathways that are thought to be the Achilles’ heel of cancer. If the targeted genes or pathways are genuinely indispensa-ble for the tumors, their inhibition should impede tumor propagation and progression. The target-specific “smart bombs” in theory should discriminatingly destroy cancer cells and leave the normal cells untouched. The very first two drugs of this kind are trastuzumab/Herceptin, a humanized monoclonal antibody against HER2/neu receptor (Baselga et partners of frequently mutated but phar-al., 1998) and Imatinib, a BCR–ABL inhibitor (Druker et al., 2001). CML patients with BCR–ABL fusion pro-tein and metastatic breast cancer patients with HER2/neu amplification showed improved response and survival rates to imatinib and trastuzumab respectively (Baselga et al., 1998; Druker et al., 2001). Unfortunately, following initial promising responses, resistance is often inevitable due to mechanisms, such as secondary muta-tions of the targets (Gorre et al., 2001) and activation of bypass pathways (Jones and Buzdar, 2009). A thorough understanding of the resistance mechanisms will facilitate the development of more effective drugs.In the recent past, targeting addictive oncoproteins, such as receptor tyrosine kinases, has overwhelmingly led drug development in the field of cancer target-specific therapies. The concept of targeting non-oncogene addiction has been investi-gated as an alternative anti-cancer therapy (Luo et al., 2009). Proteins, such as protein chaperone Hsp90 and proteasomes, them-selves are not oncogenes as they have rarely been found mutated or amplified in tumor cells. Many oncogenic proteins are often over-produced, unfolded or misfolded due to their amplification, mutations, abnormal epigenetic, or post-translational modifica-tions, etc., in tumor cells. As a result, cancer cells become addictive to Hsp90 and protea-somal functions for survival as the latter are required to fold the misfolded oncoproteins, which otherwise will be destroyed through the ubiquitination-dependent proteasome degradation pathways (Whitesell and Lindquist, 2005). Many Hsp90 and protea-some inhibitors have been generated and showed some inhibitory effects on various cancer types in preclinical and clinical set-tings (Rajkumar et al., 2005; Trepel et al., 2010). More potent and less toxic inhibitors are being actively pursued. A major chal-lenge in this field will be to identify the right cancer patients whose cancer cell survival is Hsp90- or proteasome-dependent, and to hit the targets right and hard in time with those inhibitors.The concept of “metabolic reprogram-ming or transformation” has emerged as the 7th hallmark of cancer during the past decade (Hanahan and Weinberg, 2011). Many studies suggest that the metabolic reprogramming is required for cancer cell survival and thus might be a good target for anti-cancer therapies (Tennant et al., 2010). The observation that cancer cells show increased rate of glycolysis can be traced back to as early as 1920s (Warburg, 1923). Increased glycolysis under both aerobic and anaerobic conditions promotes diversion from intracellular glucose to pyruvate, ATP, and NADH that in turn facilitate biosynthe-sis of nucleosides and amino acids required for rapid cancer cell growth and survival. Since most of the enzymes and proteins in the glycolysis pathway are ubiquitously expressed in the body, caution must be paid to selectively target tumor-specific proteins or enzyme isoforms in metabolic addiction-based target-specific therapy. Glucose trans-porter 1 (GLUT1) which is upregulated and promotes glucose import into the cells, and hexokinase which controls the first step of glycolysis and is upregulated by both HIF and Myc in many cancer types, have been explored as targets for anti-cancer therapies (Tennant et al., 2010). Challenge remains as to the identification of tumor type specific metabolic pathways so that bona fide tumor-specific targets may be used to develop more efficacious and less toxic drugs for metabolic addiction-based target-specific therapies.Different molecular networks can steer or buffer overlapping cellular processes, and disruption of one network can lead to an acquired dependency on another. An example of this is synthetic lethal interac-tion described in yeast and fruit fly, in which perturbation of two genes causes cell death (synthetic lethal) whereas perturbation of either gene alone exerts minimal or no effect on cell survival (Lucchesi, 1968; Hartman et al., 2001). With the discovery of RNA interference (RNAi), the synthetic lethal interaction idea has recently been adopted for unbiased screen for synthetic lethal macologically non-inhibitable genes, such as Ras, or tumor suppressor genes (PTEN, P53, VHL, APC, BRCA, etc.) that are deleted in tumors and thus cannot be targeted (Kaelin, 2005; Kuiken and Beijersbergen, 2010). This approach will undoubtedly lead to the discovery of novel drug targets and mechanisms of network addiction in cancer cells. It may also open an alternative way
