PI3K/AKT/mTOR Pathway Alterations Promote Malignant Progression and Xenograft Formation in Oligodendroglial Tumors.

Abstract

Oligodendroglioma has a relatively favorable prognosis, however, often undergoes malignant progression. We hypothesized that preclinical models of oligodendroglioma could facilitate identification of therapeutic targets in progressive oligodendroglioma. We established multiple oligodendroglioma xenografts to determine if the PI3K/AKT/mTOR signaling pathway drives tumor progression. 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 the relationship between PI3K/AKT/mTOR pathway alterations and oligodendroglioma xenograft formation. Pharmacologic vulnerabilities were tested in newly developed AOD models <i>in vitro</i> and <i>in vivo</i>. A specimen from the tumor site that subsequently manifested rapid clinical progression contained a <i>PIK3CA</i> mutation E542K, and yielded propagating xenografts that retained the OD/AOD-defining genomic alterations (<i>IDH1</i> ^R132H and 1p/19q codeletion) and <i>PIK3CA</i> ^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 <i>PIK3CA</i>. In our panel of OD/AOD xenografts, the presence of activating mutations in the 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, <i>P</i> < 0.0001). Importantly, mutant <i>PIK3CA</i> oligodendroglioma xenografts were vulnerable to PI3K/AKT/mTOR pathway inhibitors <i>in vitro</i> and <i>in vivo</i>-evidence that mutant <i>PIK3CA</i> is a tumorigenic driver in oligodendroglioma. Activation of the PI3K/AKT/mTOR pathway is an oncogenic driver and is associated with xenograft formation in oligodendrogliomas. These findings have implications for therapeutic targeting of PI3K/AKT/mTOR pathway activation in progressive oligodendrogliomas.