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

Authors :
Tateishi K
Nakamura T
Juratli TA
Williams EA
Matsushita Y
Miyake S
Nishi M
Miller JJ
Tummala SS
Fink AL
Lelic N
Koerner MVA
Miyake Y
Sasame J
Fujimoto K
Tanaka T
Minamimoto R
Matsunaga S
Mukaihara S
Shuto T
Taguchi H
Udaka N
Murata H
Ryo A
Yamanaka S
Curry WT
Dias-Santagata D
Yamamoto T
Ichimura K
Batchelor TT
Chi AS
Iafrate AJ
Wakimoto H
Cahill DP
Source :
Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2019 Jul 15; Vol. 25 (14), pp. 4375-4387. Date of Electronic Publication: 2019 Apr 11.
Publication Year :
2019

Abstract

Purpose: 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.<br />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 the relationship between PI3K/AKT/mTOR pathway alterations and oligodendroglioma xenograft formation. Pharmacologic vulnerabilities were tested in newly developed AOD models in vitro and in vivo .<br />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 <superscript>R132H</superscript> and 1p/19q codeletion) and PIK3CA <superscript>E542K</superscript> , 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 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, P < 0.0001). Importantly, mutant PIK3CA oligodendroglioma xenografts were vulnerable to PI3K/AKT/mTOR pathway inhibitors in vitro and in vivo -evidence that mutant PIK3CA is a tumorigenic driver in oligodendroglioma.<br />Conclusions: 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.<br /> (©2019 American Association for Cancer Research.)

Details

Language :
English
ISSN :
1557-3265
Volume :
25
Issue :
14
Database :
MEDLINE
Journal :
Clinical cancer research : an official journal of the American Association for Cancer Research
Publication Type :
Academic Journal
Accession number :
30975663
Full Text :
https://doi.org/10.1158/1078-0432.CCR-18-4144