Cellular survival pathways and resistance to cancer therapy

Chemotherapy and irradiation induce programmed cell death (apoptosis) in their target cells. Dysregulated apoptosis is a feature that is selected for during tumor formation and contributes to therapeutic resistance. Cell survival in the face of cytotoxic therapy is dictated by both internal properties of the cell, such as status of components of the apoptotic machinery, and its extracellular milieu, such as extracellular matrix (ECM) and growth factor receptor expression and signaling. The importance of extracellular survival signals as key regulators of apoptosis is now being recognized by the ability of growth factors (GFs), GF receptors (GFRs), and GFR signaling to promote cellular survival. GFs can mitigate or abrogate the effectiveness of cancer therapy and protect against other cellular insults. Because survival signals generated by different extracellular sources converge at key molecules, new molecular targets have been identified which could be exploited to maximize the effectiveness of cytotoxic cancer therapy.