Targeting hexokinase 2 enhances response to radio-chemotherapy in glioblastoma

// Alenoush Vartanian 1, * , Sameer Agnihotri 1, * , Mark R. Wilson 1 , Kelly E. Burrell 1 , Peter D. Tonge 1 , Amir Alamsahebpour 1 , Shahrzad Jalali 1 , Michael S. Taccone 1 , Sheila Mansouri 1 , Brian Golbourn 2 , Kenneth D. Aldape 1 , Gelareh Zadeh 1, 2, 3 1 MacFeeters Hamilton Center for Neuro-Oncology, Toronto, Canada 2 Arthur and Sonia Labatt Brain Tumour Research Centre, SickKids Hospital, Toronto, Canada 3 University Health Network, Toronto Western Hospital, Toronto, Canada * These authors contributed equally to this work Correspondence to: Gelareh Zadeh, email: gelareh.zadeh@uhn.on.ca Keywords: glioblastoma, metabolism, cell signaling, novel treatments Received: March 22, 2016 Accepted: August 11, 2016 Published: August 29, 2016 ABSTRACT First-line cancer therapies such as alkylating agents and radiation have limited survival benefits for Glioblastoma (GBM) patients. Current research strongly supports the notion that inhibition of aberrant tumor metabolism holds promise as a therapeutic strategy when used in combination with radiation and chemotherapy. Hexokinase 2 (HK2) has been shown to be a key driver of altered metabolism in GBM, and presents an attractive therapeutic target. To date, no study has fully assessed the therapeutic value of targeting HK2 as a mechanism to sensitize cells to standard therapy, namely in the form of radiation and temozolomide (TMZ). Using cell lines and primary cultures of GBM, we showed that inducible knockdown of HK2 altered tumor metabolism, which could not be recapitulated by HK1 or HK3 loss. HK2 loss diminished both in vivo tumor vasculature as well as growth within orthotopic intracranial xenograft models of GBMs, and the survival benefit was additive with radiation and TMZ. Radio-sensitization following inhibition of HK2 was mediated by increased DNA damage, and could be rescued through constitutive activation of ERK signaling. This study supports HK2 as a potentially effective therapeutic target in GBM.