Alterations in PTEN Insufficient to Predict Sensitivity to Drugs Targeting PI3K/mTOR Pathway


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PTEN acts as a tumor-suppressor gene through the action of its phosphatase protein product, which participates in regulation of the cell cycle to prevent too-rapid cell growth and division. Loss of PTEN function has been shown to increase PI3K/mTOR signaling, and preclinical data suggest that PTEN aberrations may be able to predict sensitivity to drugs targeting this pathway. However, Filip Janku, MD, PhD, and colleagues at The University of Texas MD Anderson Cancer Center in Houston, found that PTEN status alone did not predict response to PI3K/mTOR inhibitors in a large group of patients with diverse cancers.1

In this study, tumors from 461 patients with different cancers were scored for cytoplasmic immunohistochemical expression of PTEN, and 206 of these tumors were tested for oncogenic mutations in the MAPK pathway (ie, KRAS, NRAS, and BRAF mutations). Treatment outcomes in 153 patients receiving PI3K/mTOR inhibitors were analyzed with respect to PTEN status.

PTEN Status Does Not Predict Response

Of the 461 patients, 10% had negative PTEN expression (no staining), 36.5% had positive PTEN expression (intact staining), and 53.5% had reduced PTEN (reduced staining compared with stroma serving as a positive internal control). In tumor types with at least 10 patients tested, negative PTEN was found most frequently in uterine (10/33, 33%), renal (3/11, 27%), salivary gland (2/10, 20%), colorectal (15/82, 18%), breast (2/15, 13%), pancreatobiliary (3/24, 13%), and prostate cancers (2/19, 11%).

Of a total of 153 patients receiving therapy with PI3K/mTOR inhibitors, partial response occurred in 17 (11%), including 2 (15%) of 13 PTEN-negative patients, 3 (6%) of 50 PTEN-positive patients, and 12 (13%) of 90 patients with reduced PTEN expression. There was no significant difference in rate of partial response between PTEN-positive patients and patients with negative or reduced PTEN expression (6% vs 14%, P = .27).

MAPK Mutations More Common with Altered PTEN

While it was found that alteration of PTEN function did not predict response to treatment with PI3K/mTOR inhibitors, the investigators also found that MAPK mutations were significantly more common in patients with altered PTEN function. In particular, among the 206 patients tested, these mutations were found in 72 (50%) of 144 patients with negative or reduced PTEN expression, compared with 20 (32%) of 62 PTEN-positive patients (P = .02).

The investigators thus concluded that PTEN status alone cannot be used to predict sensitivity to PI3K/mTOR inhibitors, possibly because patients with negative or reduced PTEN expression have a greater frequency of simultaneous MAPK mutations.

Clinical Relevance

In commenting on the implications of the study, Dr. Janku stated, “We believe that these findings have considerable clinical relevance. Preclinical models have demonstrated that PTEN loss can be associated with increased PI3K/AKT/mTOR signaling and sensitivity to PI3K pathway inhibitors. However, our data suggest that this effect can be compensated for by an increased rate of MAPK pathway mutations, which can ultimately lead to therapeutic resistance. This finding warrants further investigation, since many PI3K pathway inhibitors are entering the clinical arena.”■

Disclosure: Dr. Januka has received research funding from Novartis.

Reference

1. Janku F, Broaddus R, Bakkar R, et al: PTEN assessment and PI3K/mTOR inhibitors: Importance of simultaneous assessment of MAPK pathway aberrations. 2012 ASCO Annual Meeting, Abstract 10510. Presented June 5, 2012.



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