Enhancement of cancer chemotherapy by simultaneously altering cell cycle progression and DNA-damage defenses through global modification of the serine/threonine phospho-proteome

Abstract

Despite improvements in the therapeutic efficacy of rationally designed cancer treatment regimens, most cancers remain incurable once spread beyond their sites of origin. Failure to achieve sustained control or eradication of cancers arises in large part because a subpopulation of quiescent "cancer stem cells" is insensitive to drugs targeting cell growth and replication and because defense mechanisms critical to survival of the normal cell also protect the cancer cell from cytotoxic injury. Global alteration of signal transduction by inhibition of serine/threonine dephosphorylation has recently been shown to markedly potentiate cancer cell killing by the DNA-methylating drug, temozolomide. Inhibition of the multifunctional protein phosphatase 2A appears to drive quiescent cancer cells into cycle and simultaneously inhibits cycle arrest, permitting cancer cell entry into mitosis despite the presence of chemotherapy induced DNA-damage. Absence of toxicity in animal models suggests that multi-site mutations in pathways regulating cell cycle in cancer cells make them more vulnerable than normal cells to large changes in the balance of phosphorylation-regulated signaling. Global modulation of the serine-threonine phospho-proteome may be a general method for enhancing the effectiveness of cytotoxic cancer therapy.