Pharmacological mTOR targeting enhances the antineoplastic effects of selective PI3Kα inhibition in medulloblastoma

被引:28
|
作者
Eckerdt, Frank [1 ,2 ]
Clymer, Jessica [1 ,3 ,6 ]
Bell, Jonathan B. [1 ]
Beauchamp, Elspeth M. [1 ,4 ,5 ]
Blyth, Gavin T. [1 ]
Goldman, Stewart [1 ,3 ]
Platanias, Leonidas C. [1 ,4 ,5 ]
机构
[1] Northwestern Univ, Robert H Lurie Comprehens Canc Ctr, Chicago, IL 60611 USA
[2] Northwestern Univ, Feinberg Sch Med, Dept Neurol Surg, Chicago, IL 60611 USA
[3] Ann & Robert H Lurie Childrens Hosp Chicago, Dept Pediat, Div Hematol Oncol Neuro Oncol Stem Cell Transplan, Chicago, IL 60611 USA
[4] Northwestern Univ, Feinberg Sch Med, Dept Med, Div Hematol Oncol, Chicago, IL 60611 USA
[5] Jesse Brown VA Med Ctr, Med Serv, Chicago, IL USA
[6] Dana Farber Boston Childrens Canc & Blood Disorde, Boston, MA USA
基金
美国国家卫生研究院;
关键词
CENTRAL-NERVOUS-SYSTEM; CANCER STEM-CELLS; HEDGEHOG PATHWAY; EWING SARCOMA; PI3K; BRAIN; TUMORS; PROLIFERATION; EXPRESSION; SURVIVAL;
D O I
10.1038/s41598-019-49299-3
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Despite recent advances in the treatment of medulloblastoma, patients in high-risk categories still face very poor outcomes. Evidence indicates that a subpopulation of cancer stem cells contributes to therapy resistance and tumour relapse in these patients. To prevent resistance and relapse, the development of treatment strategies tailored to target subgroup specific signalling circuits in high-risk medulloblastomas might be similarly important as targeting the cancer stem cell population. We have previously demonstrated potent antineoplastic effects for the PI3K alpha selective inhibitor alpelisib in medulloblastoma. Here, we performed studies aimed to enhance the anti-medulloblastoma effects of alpelisib by simultaneous catalytic targeting of the mTOR kinase. Pharmacological mTOR inhibition potently enhanced the suppressive effects of alpelisib on cancer cell proliferation, colony formation and apoptosis and additionally blocked sphere-forming ability of medulloblastoma stem-like cancer cells in vitro. We identified the HH effector GLI1 as a target for dual PI3K alpha and mTOR inhibition in SHH-type medulloblastoma and confirmed these results in HH-driven Ewing sarcoma cells. Importantly, pharmacologic mTOR inhibition greatly enhanced the inhibitory effects of alpelisib on medulloblastoma tumour growth in vivo. In summary, these findings highlight a key role for PI3K/mTOR signalling in GLI1 regulation in HH-driven cancers and suggest that combined PI3K alpha/mTOR inhibition may be particularly interesting for the development of effective treatment strategies in high-risk medulloblastomas.
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页数:11
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