PTEN Deficiency and PI3K family protein inhibitors

Suppressor gene linked with breast cancer treatment response
Reuters Health
Posting Date: August 23 2004
Last Updated: 2004-08-23 12:00:05 -0400 (Reuters Health)

NEW YORK (Reuters Health) - Inactivation of the tumor suppressor gene PTEN in breast cancer cells is associated with resistance to trastuzumab according to a report in the August issue of Cancer Cell.

"Currently the only clinically validated indicator for trastuzumab response is ErbB2 status " Dr. Dihua Yu from The University of Texas M.D. Anderson Cancer Center Houston Texas told Reuters Health. "Our data indicate that PTEN deficiency is a more powerful predictor for trastuzumab response than ErbB2."

Because less than 35% of patients with ErbB2-overexpressing metastatic breast cancer respond to trastuzumab therapy Dr. Yu and colleagues investigated whether the expression of PTEN an important tumor suppressor gene could predict tumor resistance to trastuzumab.

Brief treatment of cancer cells in culture with trastuzumab activated PTEN by increasing its translocation from the cytoplasm to the cell membrane the authors report.

The mechanism behind the increased membrane localization and activity appears to be the inhibition of Src binding to ErbB2 in ErbB2-overexpressing breast cancer cells leading to reduced PTEN tyrosine phosphorylation.

Cells with reduced PTEN showed significantly less growth inhibition by trastuzumab the researchers note but restoration of PTEN by inactivation of PI3K (which antagonizes PTEN function) overcame the resistance of breast cancer cells to trastuzumab.

PTEN reduction also conferred trastuzumab resistance to breast tumor xenografts in athymic nude mice the report indicates.

Moreover patients with PTEN-deficient breast cancers were significantly less likely than those with PTEN-positive tumors to have a complete or partial response to treatment with trastuzumab plus taxane the investigators report.

Dr. Yu said these results suggest that PTEN status should also be evaluated in preparation for trastuzumab treatment.

Because PI3K family protein inhibitors can help overcome PTEN-deficiency-mediated trastuzumab resistance patients who do not respond to trastuzumab alone (due to PTEN-deficiency) may benefit from trastuzumab used in combination with a PI3K family protein inhibitor Dr. Yu said.

"This needs to be validated in a well-designed clinical trial which [our] Breast Medical Oncology Department is planning to do " Dr. Yu concluded.

"For optimal success matching individual tumor signaling anomalies with a customized treatment strategy will ultimately provide the most effective way to take advantage of the ever-increasing list of new biological therapies for cancer " write Dr. Robert J. Crowder and colleagues from Washington University School of Medicine St. Louis Missouri in a related editorial.

Cancer Cell 2004;6:103-104 117-127.