Study identifies molecular switch that integrates cell survival signals from multiple intracellular signaling pathways

A new study published in the October issue of Cancer Cell identifies a molecular switch that integrates cell survival signals from multiple intracellular signaling pathways.

The finding has substantial clinical significance, as mutations in these cell survival-signaling pathways are associated with many human cancers, and a better understanding of how these pathways converge to regulate the delicate balance between cell proliferation and cell death may lead to development of more effective cancer therapies.

A complex interplay between growth signals and apoptosis (programmed cell death) regulates cell proliferation. Activation of the epidermal growth factor receptor (EGFR) inhibits apoptosis, and EGFR mutations are associated with some human cancers. However, inhibition of EGFR expression has not been widely successful as a cancer treatment because, in many cases, mutations occur in signaling molecules downstream of EGFR, such as the tumor suppressor PTEN. Dr. Neal Rosen and colleagues from Memorial Sloan-Kettering Cancer Center in New York examined interplay between cell proliferation signals in tumor cells with PTEN mutations.

The loss of the PTEN tumor suppressor gene results in constitutive activation of Akt, a molecule that promotes cell survival independently of EGFR. Tumor cells with mutated PTEN did not respond to treatment with EGFR inhibitors, but when PTEN activity was restored, tumor cells were sensitized to treatment with EGFR inhibitors. Importantly, both EGFR and Akt inhibit the activity of BAD, a molecule that drives apoptosis, and activation of either EGFR or Akt alone is sufficient to inhibit BAD and block cell death. The researchers further demonstrated that mice with tumors displaying PTEN mutations did not respond to either EGFR or Akt inhibition alone but that combined therapy resulted in significant tumor regression.

The results indicate that BAD acts as a switch that integrates the antiapoptotic effects of multiple pathways enhancing cell survival in PTEN-deficient tumor cells. "The data provide a heuristic model for understanding pathway interactions that allows the development of rational strategies for combination therapy and reveals a potential clinical role for inhibition of wild-type EGFR. Thus, EGFR inhibitors may be useful in combination with inhibitors of PI3K/Akt kinase signaling for the treatment of glioblastomas, prostate cancer, and other tumors in which EGFR activation and PTEN mutation coexist," explains Dr. Rosen.