PI3K/AKT/mTOR pathway alterations promote malignant progression and xenograft formation in oligodendroglial tumors

Abstract

Purpose:

Oligodendroglioma (OD) has a relatively favorable prognosis, however, often undergoes malignant progression. We hypothesized that preclinical models of OD could facilitate identification of therapeutic targets in progressive OD. We established multiple OD xenografts to determine if PI3K/AKT/mTOR signaling pathway drives tumor progression.

Experimental Design:

Two anatomically distinct tumor samples from a patient who developed progressive anaplastic oligodendroglioma (AOD), were collected for orthotopic transplantation in mice. We additionally implanted 13 tumors to investigate relationship between PI3K/AKT/mTOR pathway alterations and OD xenograft formation. Pharmacologic vulnerabilities were tested in newly developed AOD models in vitro and in vivo.

Results:

A specimen from the tumor site that subsequently manifested rapid clinical progression contained a PIK3CA mutation E542K, and yielded propagating xenografts that retained the OD/AOD-defining genomic alterations ( IDH1 ^R132H and 1p/19q co-deletion) and PIK3CA ^E542K, and displayed characteristic sensitivity to alkylating chemotherapeutic agents. In contrast, a xenograft did not engraft from the region that was clinically stable and had wild-type PIK3CA. In our panel of OD/AOD xenografts, the presence of activating mutations in PI3K/AKT/mTOR pathway was consistently associated with xenograft establishment (6/6, 100%). OD/AOD that failed to generate xenografts did not have activating PI3K/AKT/mTOR alterations (0/9, p<0.0001). Importantly, mutant PIK3CA OD xenografts were vulnerable to PI3K/AKT/mTOR pathway inhibitors in vitro and in vivo, evidence that mutant PIK3CA is a tumorigenic driver in OD.

Conclusions:

Activation of the PI3K/AKT/mTOR pathway is an oncogenic driver and is associated with xenograft formation in ODs. These findings have implications for therapeutic targeting of PI3K/AKT/mTOR pathway activation in progressive ODs.