, Analysis and interpretations of data: Moukengue, B; Brown HK

S. Battaglia, M. Baud'huin, T. Quillard, U. Berglund, and D. Heymann, , p.631

T. Helleday, B. Ory, and F. Lamoureux,

, Writing, review, and/or revision of the manuscript: Moukengue, B; Brown HK, p.633

T. Quillard, U. Berglund, D. ;-heymann, T. Helleday, B. Ory et al.,

F. Lamoureux, V. Trichet, C. Chipoy, F. Blanchard, F. Gouin et al., Recent advances in the 642 management of osteosarcoma and forthcoming therapeutic strategies, Expert Rev Anticancer Ther, vol.643, issue.2, pp.169-81, 2007.

G. Rosen, M. L. Murphy, A. G. Huvos, M. Gutierrez, and R. C. Marcove, Chemotherapy, en bloc resection, 645 and prosthetic bone replacement in the treatment of osteogenic sarcoma, Cancer, vol.37, issue.1, pp.1-11, 1976.

J. A. Lee, Osteosarcoma in Korean children and adolescents, Korean J Pediatr, vol.58, issue.4, pp.123-647, 2015.

J. P. He, Y. Hao, X. L. Wang, X. J. Yang, J. F. Shao et al., Review of the molecular pathogenesis 649 of osteosarcoma, Asian Pac J Cancer Prev, vol.15, issue.15, pp.5967-76, 2014.

H. K. Brown, K. Schiavone, F. Gouin, M. F. Heymann, and D. Heymann, Biology of Bone Sarcomas and 651 New Therapeutic Developments, Calcif Tissue Int, vol.102, issue.2, pp.174-95, 2018.

L. S. Goodman and M. M. Wintrobe, Nitrogen mustard therapy; use of methyl-bis (beta-653 chloroethyl) amine hydrochloride and tris (beta-chloroethyl) amine hydrochloride for Hodgkin's 654 disease, lymphosarcoma, leukemia and certain allied and miscellaneous disorders, J Am Med Assoc, vol.655, pp.126-158, 1946.

S. Farber, Some observations on the effect of folic acid antagonists on acute leukemia and 657 other forms of incurable cancer, Blood, vol.4, issue.2, pp.160-167, 1949.

K. Cheung-ong, G. Giaever, and C. Nislow, DNA-damaging agents in cancer chemotherapy: 659 serendipity and chemical biology, Chem Biol, vol.20, issue.5, pp.648-59, 2013.

H. J. Park, J. S. Bae, K. M. Kim, Y. J. Moon, S. H. Park et al., The PARP inhibitor olaparib 661 potentiates the effect of the DNA damaging agent doxorubicin in osteosarcoma, J Exp Clin Cancer 662 Res, vol.37, issue.1, p.107, 2018.

Z. Zou, H. Chang, H. Li, and S. Wang, Induction of reactive oxygen species: an emerging approach for 664 cancer therapy, Apoptosis, vol.22, issue.11, p.11, 2017.

Y. Nakabeppu, S. Oka, Z. Sheng, D. Tsuchimoto, and K. Sakumi, Programmed cell death triggered by 666 nucleotide pool damage and its prevention by MutT homolog-1 (MTH1) with oxidized purine 667 nucleoside triphosphatase, Mutat Res, vol.703, issue.1, p.12, 2010.

Y. Nakabeppu, E. Ohta, and N. Abolhassani, MTH1 as a nucleotide pool sanitizing enzyme: Friend or 669 foe?, Free Radic Biol Med, vol.107, pp.151-159, 2017.

K. Fujikawa, H. Kamiya, H. Yakushiji, Y. Nakabeppu, and H. Kasai, Human MTH1 protein hydrolyzes 671 the oxidized ribonucleotide, 2-hydroxy-ATP, Nucleic Acids Res, vol.29, issue.2, p.14, 2001.

G. Pizzino, N. Irrera, M. Cucinotta, G. Pallio, F. Mannino et al., Oxidative Stress: 673 Harms and Benefits for Human Health, Oxid Med Cell Longev, vol.674, p.15, 2017.

G. Y. Liou and P. Storz, Reactive oxygen species in cancer, Free Radic Res, vol.44, issue.5, p.16, 2010.

J. N. Moloney and T. G. Cotter, ROS signalling in the biology of cancer, Semin Cell Dev Biol, vol.676, p.17, 2018.

P. Storz, Reactive oxygen species in tumor progression, Front Biosci, vol.10, pp.1881-96, 2005.

E. Coskun, P. Jaruga, A. S. Jemth, O. Loseva, L. D. Scanlan et al., Addiction to MTH1 protein 679 results in intense expression in human breast cancer tissue as measured by liquid chromatography-680 isotope-dilution tandem mass spectrometry, DNA Repair (Amst), vol.33, p.19, 2015.

T. Obtulowicz, M. Swoboda, E. Speina, D. Gackowski, R. Rozalski et al., Oxidative stress 682 and 8-oxoguanine repair are enhanced in colon adenoma and carcinoma patients, Mutagenesis, vol.683, issue.5, pp.463-71, 2010.

T. Tsuzuki, A. Egashira, H. Igarashi, T. Iwakuma, Y. Nakatsuru et al., Spontaneous 685 tumorigenesis in mice defective in the MTH1 gene encoding 8-oxo-dGTPase, Proc Natl Acad Sci, vol.98, issue.20, pp.11456-61, 2001.

H. Gad, T. Koolmeister, A. S. Jemth, S. Eshtad, S. A. Jacques et al., MTH1 inhibition 688 eradicates cancer by preventing sanitation of the dNTP pool, Nature, vol.508, issue.7495, p.22, 2014.

W. Berglund, U. Sanjiv, K. Gad, H. Kalderen, C. Koolmeister et al., Validation 690 and development of MTH1 inhibitors for treatment of cancer, Ann Oncol, vol.27, issue.12, p.23, 2016.

K. V. Huber, E. Salah, B. Radic, M. Gridling, J. M. Elkins et al., Stereospecific targeting of 692 MTH1 by (S)-crizotinib as an anticancer strategy, Nature, vol.508, issue.7495, p.24, 2014.

X. Qing, Z. Shao, X. Lv, F. Pu, F. Gao et al., Anticancer effect of (S)-crizotinib on 694 osteosarcoma cells by targeting MTH1 and activating reactive oxygen species, Anticancer Drugs, vol.695, issue.4, p.25, 2018.

T. Kawamura, M. Kawatani, M. Muroi, Y. Kondoh, Y. Futamura et al., Proteomic profiling 697 of small-molecule inhibitors reveals dispensability of MTH1 for cancer cell survival, J Med Chem, vol.698, issue.6, p.27, 2016.

G. J. Samaranayake, M. Huynh, and P. Rai, MTH1 as a Chemotherapeutic Target: The Elephant in the 702 Room, Cancers (Basel), vol.9, issue.5, 2017.

A. Petrocchi, E. Leo, N. J. Reyna, M. M. Hamilton, X. Shi et al., Identification of potent 704 and selective MTH1 inhibitors, Bioorg Med Chem Lett, vol.26, issue.6, p.29, 2016.

M. Baud'huin, F. Lamoureux, C. Jacques, R. Calleja, L. Quillard et al., 706 Inhibition of BET proteins and epigenetic signaling as a potential treatment for osteoporosis, Bone, vol.707, p.30, 2017.

P. Rai, T. T. Onder, J. J. Young, J. L. Mcfaline, B. Pang et al., Continuous elimination of 709 oxidized nucleotides is necessary to prevent rapid onset of cellular senescence, Proc Natl Acad Sci, vol.106, issue.1, pp.169-74, 2009.

L. Struthers, R. Patel, J. Clark, and S. Thomas, Direct detection of 8-oxodeoxyguanosine and 8-712 oxoguanine by avidin and its analogues, Anal Biochem, vol.255, issue.1, p.32, 1998.

M. Molina, D. Jafari, R. Ignatushchenko, M. Seki, T. Larsson et al., Monitoring 714 drug target engagement in cells and tissues using the cellular thermal shift assay, Science, vol.715, issue.6141, pp.84-91, 2013.

S. Burma, B. P. Chen, M. Murphy, A. Kurimasa, and D. J. Chen, ATM phosphorylates histone H2AX in 717 response to DNA double-strand breaks, J Biol Chem, vol.276, issue.45, p.34, 2001.

A. Georgoulis, C. E. Vorgias, G. P. Chrousos, and E. P. Rogakou, Genome Instability and gammaH2AX. Int 719, J Mol Sci, vol.18, issue.9, 2017.

P. Rai, J. J. Young, D. G. Burton, M. G. Giribaldi, T. T. Onder et al., Enhanced elimination of 721 oxidized guanine nucleotides inhibits oncogenic RAS-induced DNA damage and premature 722 senescence, Oncogene, vol.30, issue.12, p.36, 2011.

T. Helleday, Cancer phenotypic lethality, exemplified by the non-essential MTH1 enzyme 724 being required for cancer survival, Ann Oncol, vol.25, issue.7, p.37, 2014.

L. Pudelko, P. Rouhi, K. Sanjiv, H. Gad, C. Kalderen et al., Glioblastoma and 726 glioblastoma stem cells are dependent on functional MTH1, Oncotarget, vol.8, issue.49, p.38, 2017.

W. Zhou, L. Ma, J. Yang, H. Qiao, L. Li et al., Potent and specific MTH1 inhibitors targeting 728 gastric cancer, Cell Death Dis, vol.10, issue.6, pp.434-729, 2019.

H. Gad, O. Mortusewicz, S. G. Rudd, A. Stolz, N. Amaral et al., MTH1 promotes 730 mitotic progression to avoid oxidative DNA damage in cancer cells, bioRxiv, vol.575290, p.40, 2019.

H. Abbas, K. Alhamoudi, M. D. Evans, G. Jones, S. S. Foster et al., MTH1 deficiency selectively 732 increases non-cytotoxic oxidative DNA damage in lung cancer cells: more bad news than good? BMC 733 Cancer, vol.18, 2018.

M. Pompsch, J. Vogel, F. Classen, P. Kranz, G. Iliakis et al., The presumed MTH1-738 inhibitor TH588 sensitizes colorectal carcinoma cells to ionizing radiation in hypoxia, 736 Sci Rep, vol.9, issue.1, p.1190, 2018.

C. Redon, D. Pilch, E. Rogakou, O. Sedelnikova, K. Newrock et al., Histone H2A variants 741 H2AX and H2AZ, Curr Opin Genet Dev, vol.12, issue.2, p.44, 2002.

A. Chalopin, M. Tellez-gabriel, H. K. Brown, F. Vallette, M. F. Heymann et al., Isolation of 743 circulating tumor cells in a preclinical model of osteosarcoma: Effect of chemotherapy, J Bone Oncol, vol.744, p.45, 2018.

M. Li, Y. Lu, Z. Long, M. Li, J. Kong et al., Prognostic and clinicopathological significance 746 of circulating tumor cells in osteosarcoma, J Bone Oncol, vol.16, p.46, 2019.

K. D. Arczewska, A. Stachurska, M. Wojewodzka, K. Karpinska, M. Kruszewski et al., 748 hMTH1 is required for maintaining migration and invasion potential of human thyroid cancer cells, DNA Repair (Amst), vol.749, pp.53-62, 2018.