Abstract Abstract #ES-6 The cellular and molecular processes that lead to cancer, include self-sufficiency in growth signals, insensivity to anti-growth factor signals, evasion of apoptosis, lack of senescence, invasion and metastasis, and sustained angiogenesis. All these processes can be potentially targeted with a variety of therapeutic strategies that include, in addition to anti-HER2 therapies, the following classes of agents:
 1. Growth factor receptor signaling pathways
 1.1. Inhibitors of PI3K/Akt pathway
 The frequent dysregulation of the PI3K/Akt/mTOR pathway in human breast cancer has made components of this pathway attractive for therapeutic targeting. Clinical trials are currently underway with mTOR, PI3K, and Akt inhibitors.
 1.2. Src-family Tyrosine Kinases Inhibitors
 Src is a non-receptor signaling kinase that functions at the hub of a vast array of signal transduction pathways that influence cellular proliferation, differentiation, motility, and survival. In addition, Src activity also mediates epithelial-to-mesenchymal transition. Src inhibitors are in clinical development either given alone or in combination with other therapies. As with other kinase inhibitors, src inhibitors differ among themselves by their specificity.
 1.3. RAF/MEK/MAPK(ERK) Pathway Inhibitors
 The RAS proteins are members of a large superfamily of GTP-binding proteins that play a complex role in the normal transduction of growth factor receptor-induced signals. Different agents have been developed to target the Ras/Raf/MAPK(ERK) pathway due to the aberrant activation of this pathway in a large number of human tumors. These agents include farnesyltransferase inhibitors, Raf inhibitors, and MEK/MAPK inhibitors.
 1.4. Heat Shock Protein (Hsp) 90 Inhibitors
 Hsp90 is a molecular chaperone that is required for the refolding of proteins under conditions of environmental stress and for the conformational maturation of a subset of key signaling proteins. Many of these client proteins such as AKT, HER2, c-KIT, EGFR and PDGFR-α are oncoproteins and important cell-signaling proteins deregulated in cancer. In the clinic, initial studies with HSP90 inhibitors have demonstrated anti-tumor activity and tolerability in patients with trastuzumab-refractory HER2-positive metastatic breast cancer patients.
 2. DNA-repair interfering agents. PARP-1 Inhibitors
 PARP inhibitors have been shown to enhance, in human cancer cell models, the antitumor activity of DNA-methylating agents and to restore sensitivity of tumors resistant to methylating agents or topoisomerase I inhibitors, two classes of agents being used for the treatment of breast cancer. Initial phase I studies with the PARP inhibitors have shown to be safety and clinical activity in patients with an inherited mutation in one of the cancer genes, BRCA1 or BRCA2.
 3. Targeting Programmed Cell Death (Apoptosis)
 Evasion of apoptosis is associated with many human cancers and is one of the hallmarks of the malignant phenotype and may play a role in the observed chemoradioresistance that occurs in many tumors. TRAIL receptor agonists are currently entering clinical trials in patients with breast cancer. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr ES-6.