Control of oncogenesis and cancer therapy resistance

Abstract

Despite the combined action of surgery, radiotherapy and chemotherapy, the leading cause of death in cancer patients continues to be the acquired, or intrinsic, tumour resistance to therapy. Some of the genetic alterations that contribute to the malignant transformation are involved in maintaining cell survival under uncontrolled growth conditions. Chemotherapy agents, as well as radiotherapy, trigger a series of signalling pathways in the cells that activate not only the apoptotic machinery, but also cell-survival pathways. In this scenario, the efficacy of therapy is the result of balance between the apoptotic and the survival pathways activated in the tumour, and those elicited by the therapeutic agent. Apoptosis is one of the programmes usually altered in most cancers so as to guarantee tumour progression and, often, these alterations are responsible for therapy resistance, as well.

Figure 1

Combination therapy would shift the balance towards apoptosis in the response of drug-resistant tumours. Note: In normal cells, the balance among apoptosis and survival signals allow controlled homeostasis of the tissue. In cancer cells, survival signals triggered by oncogenic transformation favour uncontrolled growth. Traditional treatments such as chemotherapy and radiotherapy, together with targeted therapies, are still not sufficient to kill tumour cells efficiently due to the existence of antiapoptotic mechanisms in the tumour. Reactivation of the apoptotic machinery by strategies such as Apo2/TRAIl delivery would, probably, make the combination of traditional and targeted therapies more efficient.