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The novel ATM inhibitor (AZ31) enhances antitumor activity in patient derived xenografts that are resistant to irinotecan monotherapy

2017; Impact Journals LLC; Volume: 8; Issue: 67 Linguagem: Inglês

10.18632/oncotarget.22920

1949-2553

Justin Greene, Anna Nguyen, Stacey M. Bagby, Gemma N. Jones, WM. Tai, Kevin S. Quackenbush, Anna Schreiber, Wells A. Messersmith, Kalpana Devaraj, Patrick J. Blatchford, S. Gail Eckhardt, Elaine Cadogan, Gareth Hughes, Aaron Smith, Todd M. Pitts, John J. Arcaroli,

DNA Repair Mechanisms

// Justin Greene 1, * , Anna Nguyen 1, * , Stacey M. Bagby 1 , Gemma N. Jones 4 , WM. Tai 1, 3 , Kevin S. Quackenbush 1 , Anna Schreiber 1 , Wells A. Messersmith 1 , Kalpana M. Devaraj 2 , Patrick Blatchford 1 , S. Gail Eckhardt 1 , Elaine B. Cadogan 4 , Gareth D. Hughes 4 , Aaron Smith 4 , Todd M. Pitts 1 and John J. Arcaroli 1 1 Division of Medical Oncology, University of Colorado Anschutz Medical Campus and University of Colorado Cancer Center, Aurora, CO, USA 2 Pathology Department, University of Colorado Anschutz Medical Campus, Aurora, CO, USA 3 Division of Medical Oncology, National Cancer Centre Singapore, Singapore 4 Innovative Medicines and Early Development, Oncology, AstraZeneca, Cambridge, UK * These authors contributed equally to this work Correspondence to: John J. Arcaroli, email: john.arcaroli@ucdenver.edu Keywords: ATM; DNA damage; IRN; PDTX; CRC Received: August 06, 2017 Accepted: November 09, 2017 Published: December 05, 2017 ABSTRACT Irinotecan, a standard of care therapy for CRC, elicits cytotoxic effects by generating double strand breaks resulting in DNA damage. The activation of the ATM pathway plays a fundamental role in regulating the cellular response and repair to DNA damage. The objective of this preclinical study was to determine whether ATM inhibition would enhance sensitivity to irinotecan treatment. Treatment effects of AZ31, irinotecan or AZ31 + irinotecan were investigated in CRC cell lines and CRC patient derived xenografts. Activation of ATM and downstream targets p-RAD50 and p-H2AX were evaluated by immunohistochemistry. Combinational effects were demonstrated in 4 out of 8 CRC explants. Interestingly, each of the combinational sensitive CRC PDX models were shown to be more resistant to irinotecan single agent therapy. Treatment with irinotecan significantly elevated the ATM pathway evident by an increase in the activation of H2AX and RAD50. Combinational therapy reduced the activation of H2AX and RAD50 when compared to irinotecan alone in the combination sensitive CRC098. AZ31 + irinotecan was effective at reducing tumor growth in tumors that exhibited resistance to irinotecan in our CRC PDX model. These findings support further investigation of this combinational therapy for the treatment of CRC patients.