Dr. Bakkenist is an Associate Professor of Radiation Oncology, and Pharmacology and Chemical Biology and the Associate Director for Education and Training at UPMC Hillman Cancer Center.
Vendetti FP, Karukonda P, Clump DA, Teo T, Lalonde R, Nugent K, Ballew M, Kiesel BF, Beumer JH, Sarkar SN, Conrads TP, O’Connor MJ, Ferris RL, Tran PT, Delgoffe GM, Bakkenist CJ. (2018) ATR kinase inhibitor AZD6738 potentiates CD8+ T cell activity in the tumor microenvironment following radiation. Journal of Clinical Investigation, in press
Moiseeva T, Hood B, Schamus S, O’Connor MJ, Conrads TP, Bakkenist CJ (2017) ATR kinase inhibition induces unscheduled origin firing through a Cdc7-dependent association between GINS and And-1. Nature Communications 8, 1392. PMID: 29123096; PMCID: PMC 5680267
Vendetti FP, Leibowitz BJ, Barnes J, Schamus S, Kiesel BF, Abberbock S, Conrads T, Clump DA, Cadogan E, O’Connor MJ, Yu J, Beumer JH, Bakkenist CJ. (2017) Pharmacologic ATM but not ATR kinase inhibition abrogates p21-dependent G1 arrest and promotes gastrointestinal syndrome after total body irradiation. Scientific Reports, 7, 41892. PMID: 28145510; PMCID: PMC 5286430.
Villaruz L, Jones H, Dacic S, Abberbock S, Kurland BF, Stabile LP, Siegfried JM, Conrad TP, Smith NR, O’Connor MJ, Pierce AJ, Bakkenist CJ. (2016) ATM protein is deficient in over 40% of lung adenocarcinomas. Oncotarget 7, 57714-57725. PMID: 27259260; PMCID: PMC5295384.
Moiseeva TN, Gamper AM, Hood BL, Conrads TP, Bakkenist CJ. (2016) Human DNA polymerase e is phosphorylated at serine-1940 after DNA damage and interacts with the iron-sulphur complex chaperones CIAO1 and MMS19. DNA Repair 43, 9-17. PMID: 27235625; PMCID: PMC4917431
Vendetti FP, Lau A, Schamus S, Conrads TP, O’Connor MJ, Bakkenist CJ. (2015) The orally active and bioavailable ATR kinase inhibitor AZD6738 potentiates the anti-tumor effects of cisplatin to resolve ATM-deficient non-small cell lung cancer in vivo. Oncotarget, 6, 44289-44305. PMID: 26517239; PMCID: PMC4792557
Gamper AM, Rofougaran R, Watkins SC, Greenberger JS, Beumer JH, Bakkenist CJ. (2013) ATR kinase activation in G1 phase facilitates the repair of ionizing radiation-induced DNA damage. Nucleic Acids Research 41, 10334-10344. PMID: 24038466; PMCID: PMC3905881
Bakkenist CJ, Czambel RK, Clump DA, Greenberger JS, Beumer JH and Schmitz JC (2013) Radiation therapy induces the DNA damage response in peripheral blood. Oncotarget 4, 1143-1148. PMID: 23900392; PMCID: PMC3787146
Choi S, Srivas R, Fu KY, Hood BL, Dost B, Gibson GA, Watkins SC, Van Houten B, Bandeira N, Conrads TP, Ideker T, Bakkenist CJ. (2012) Quantitative proteomics reveal ATM kinase-dependent exchange in DNA damage response complexes. Journal of Proteome Research 11, 4983-4991. PMID: 22909323; PMCID: PMC3495236
Gamper AM, Choi S, Matsumoto M, Banerjee D, Tomkinson AE, Bakkenist CJ. (2012) ATM protein physically and functionally interacts with PCNA to regulate DNA synthesis. Journal of Biological Chemistry 287, 12445-12454. PMID: 22362778; PMCID: PMC3320994
White JS, Choi S, Bakkenist CJ. (2010) Transient ATM kinase inhibition disrupts DNA damage-induced sister chromatid exchange. Science Signaling 3, ra44. PMID: 20516478; PMCID: PMC3261617
Bakkenist CJ, Kastan MB. (2003) DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation. Nature 421, 499-506. PMID: 12556884 * article cited >2,000 times
ATM and ATR are DNA damage signaling kinases that regulate DNA replication and homologous recombination repair. Pharmacologic inhibitors of ATM and ATR kinase activity have been developed and these are predicted to increase the efficacy of genotoxic chemotherapy. A primary focus of the Bakkenist laboratory is to determine the mechanistic consequences of ATM and ATR kinase inhibition. The laboratory showed that ATM kinase inhibition does not phenocopy ATM protein disruption, and generated the paradigm that transient ATM kinase inhibition poisons DNA damage repair complexes generating persistent chromatid breaks. These findings are important in the clinical setting where ATM kinase inhibitors will only be effective for several hours. The laboratory showed that ATR kinase activity is not restricted to S phase cells and that ATR kinase is activated in all phases of the cell cycle after exposure to ionizing radiation. Recently, the laboratory discovered the ATR kinase-dependent mechanism that inhibits dormant origin firing in mammalian cells. This is a fundamental mechanism of genome stability that evolved with chromosomes that contain more than one origin. This finding is important in the clinical setting as ATR kinase inhibitor-induced origin firing generates additional replication forks that are targeted by DNA damaging agents. Thus, the sequence of administration of an ATR kinase inhibitor and a DNA damaging agent impacts the DNA damage induced by the combination.
DNA damage signaling to immune checkpoints
Pre-clinical cancer research in the Bakkenist laboratory determined that ATR kinase inhibitors are well-tolerated and that the combination of ATR kinase inhibitor and cisplatin generates durable responses in mouse xenograft models of lung cancer. The laboratory also showed that the combination of ATR kinase inhibitor and conformal radiation generates a complete response in an immunoproficient, genetically engineered mouse model of lung cancer and syngeneic models of colorectal cancer and that these responses require CD8+ T cells. The laboratory subsequently discovered unexpected crosstalk between ATR kinase signaling and immune checkpoints. Remarkably, tumor bearing mice cured by the combination of ATR kinase inhibitor and conformal radiation acquire immunologic memory and are resistant to tumor re-challenge.
The Bakkenist laboratory collaborates with AstraZeneca and UPMC Hillman Cancer Center Radiation, Surgical and Medical Oncologists to design and complete Phase I and Phase II clinical trials. The laboratory’s pre-clinical research was essential for the election of Liza Villaruz, MD, Jan Beumer, Pharm D, Ed Chu, MD and Chris Bakkenist, PhD as members of the NCI/CTEP/UM1 VX-970 ATR inhibitor Clinical Trials Design Team Project Team. Hillman was selected as the lead site for ATR Kinase Inhibitor VX-970 and Irinotecan Hydrochloride trial in all comers. Our clinical work identified the phosphorylation of ATM serine-1981 in peripheral blood mononuclear cells (PBMCs) as a clinical biomarker for target engagement. Hillman is completing a trial of this phosphorylation as a biomarker for radiation toxicity in head and neck cancer. In 2018, Hillman enrolled and treated the first patients with an ATM kinase inhibitor and the phosphorylation of ATM serine-1981 in PBMCs is a mandatory biomarker for all patients on this trial.