{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,6]],"date-time":"2026-04-06T21:49:58Z","timestamp":1775512198105,"version":"3.50.1"},"reference-count":53,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2022,5,21]],"date-time":"2022-05-21T00:00:00Z","timestamp":1653091200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006692","name":"University of Turin","doi-asserted-by":"publisher","award":["DIRM_CT_RIC_17_01"],"award-info":[{"award-number":["DIRM_CT_RIC_17_01"]}],"id":[{"id":"10.13039\/501100006692","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The MET oncogene encodes a tyrosine kinase (TK) receptor. Its activation protects cells from death but also stimulates DNA damage response by triggering excess replicative stress. Transcriptomic classification of cancer cell lines based on MET expression showed that response to the PARP inhibitor (PARPi) olaparib is poorer in MET overexpressing cell lines. Accordingly, a high MET expressing lung carcinoma cell line was sensitized to PARPi by MET TK inhibition. This was not linked solely to MET overexpression: other MET overexpressing cell lines were biochemically but not functionally responsive to combined inhibition. Moreover, exogenously induced MET overexpression was unable to induce resistance to PARPi. The MET overexpressing cell line, responsive to the combined PARP and MET inhibition, carried a heterozygous mutation of the ATM gene and showed an attenuated response of ATM to PARPi. Among the downstream targets of ATM activation, NuMA was phosphorylated only in response to the combined PARP and MET inhibition. Given the role played by NuMA in mitosis, data show that the latter is affected by MET and PARP inhibition in cells with haploinsufficient ATM. This is important as ATM heterozygous mutation is frequently found in human cancer and in lung carcinomas in particular.<\/jats:p>","DOI":"10.3390\/ijms23105770","type":"journal-article","created":{"date-parts":[[2022,5,21]],"date-time":"2022-05-21T09:18:08Z","timestamp":1653124688000},"page":"5770","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Cancer Cells Haploinsufficient for ATM Are Sensitized to PARP Inhibitors by MET Inhibition"],"prefix":"10.3390","volume":"23","author":[{"given":"Concetta","family":"D\u2019Ambrosio","sequence":"first","affiliation":[{"name":"Candiolo Cancer Institute, FPO-IRCCS, 10060 Candiolo, Italy"},{"name":"Department of Oncology, University of Torino, 10129 Torino, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7152-0930","authenticated-orcid":false,"given":"Jessica","family":"Erriquez","sequence":"additional","affiliation":[{"name":"Candiolo Cancer Institute, FPO-IRCCS, 10060 Candiolo, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sonia","family":"Capellero","sequence":"additional","affiliation":[{"name":"Candiolo Cancer Institute, FPO-IRCCS, 10060 Candiolo, Italy"},{"name":"Department of Oncology, University of Torino, 10129 Torino, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Simona","family":"Cignetto","sequence":"additional","affiliation":[{"name":"Candiolo Cancer Institute, FPO-IRCCS, 10060 Candiolo, Italy"},{"name":"Department of Oncology, University of Torino, 10129 Torino, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria","family":"Alvaro","sequence":"additional","affiliation":[{"name":"Candiolo Cancer Institute, FPO-IRCCS, 10060 Candiolo, Italy"},{"name":"Department of Oncology, University of Torino, 10129 Torino, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3856-6435","authenticated-orcid":false,"given":"Eric","family":"Ciamporcero","sequence":"additional","affiliation":[{"name":"OCTIMET Oncology NV, 2340 Beerse, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria Flavia","family":"Di Renzo","sequence":"additional","affiliation":[{"name":"Candiolo Cancer Institute, FPO-IRCCS, 10060 Candiolo, Italy"},{"name":"Department of Oncology, University of Torino, 10129 Torino, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Timothy","family":"Perera","sequence":"additional","affiliation":[{"name":"OCTIMET Oncology NV, 2340 Beerse, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5444-6305","authenticated-orcid":false,"given":"Giorgio","family":"Valabrega","sequence":"additional","affiliation":[{"name":"Candiolo Cancer Institute, FPO-IRCCS, 10060 Candiolo, Italy"},{"name":"Department of Oncology, University of Torino, 10129 Torino, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Martina","family":"Olivero","sequence":"additional","affiliation":[{"name":"Candiolo Cancer Institute, FPO-IRCCS, 10060 Candiolo, Italy"},{"name":"Department of Oncology, University of Torino, 10129 Torino, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,5,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Faraoni, I., and Graziani, G. (2018). Role of BRCA Mutations in Cancer Treatment with Poly(ADP-ribose) Polymerase (PARP) Inhibitors. Cancers, 10.","DOI":"10.3390\/cancers10120487"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"913","DOI":"10.1038\/nature03443","article-title":"Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase","volume":"434","author":"Bryant","year":"2005","journal-title":"Nature"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"917","DOI":"10.1038\/nature03445","article-title":"Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy","volume":"434","author":"Farmer","year":"2005","journal-title":"Nature"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1070","DOI":"10.1016\/j.molcel.2020.04.035","article-title":"Biomarker-Guided Development of DNA Repair Inhibitors","volume":"78","author":"Cleary","year":"2020","journal-title":"Mol. Cell"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1137","DOI":"10.1158\/2159-8290.CD-15-0714","article-title":"Homologous Recombination Deficiency: Exploiting the Fundamental Vulnerability of Ovarian Cancer","volume":"5","author":"Konstantinopoulos","year":"2015","journal-title":"Cancer Discov."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1016\/j.dnarep.2018.08.021","article-title":"Mechanisms of PARP inhibitor sensitivity and resistance","volume":"71","year":"2018","journal-title":"DNA Repair"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1093\/emboj\/19.3.463","article-title":"The controlling role of ATM in homologous recombinational repair of DNA damage","volume":"19","author":"Morrison","year":"2000","journal-title":"EMBO J."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1038\/s41467-018-07729-2","article-title":"ATM orchestrates the DNA-damage response to counter toxic non-homologous end-joining at broken replication forks","volume":"10","author":"Balmus","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1016\/j.molcel.2017.05.015","article-title":"ATM, ATR, and DNA-PK: The Trinity at the Heart of the DNA Damage Response","volume":"66","author":"Blackford","year":"2017","journal-title":"Mol. Cell"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1160","DOI":"10.1126\/science.1140321","article-title":"ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage","volume":"316","author":"Matsuoka","year":"2007","journal-title":"Science"},{"key":"ref_11","first-page":"159","article-title":"Ataxia-telangiectasia: Future prospects","volume":"7","author":"Chaudhary","year":"2014","journal-title":"Appl. Clin. Genet."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1038\/nrg3539","article-title":"Emerging patterns of somatic mutations in cancer","volume":"14","author":"Watson","year":"2013","journal-title":"Nat. Rev. Genet."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1781","DOI":"10.1158\/1535-7163.MCT-15-0945","article-title":"ATM Mutations in Cancer: Therapeutic Implications","volume":"15","author":"Choi","year":"2016","journal-title":"Mol. Cancer Ther."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"R435","DOI":"10.1016\/j.cub.2014.04.012","article-title":"DNA replication and oncogene-induced replicative stress","volume":"24","author":"Hills","year":"2014","journal-title":"Curr. Biol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"4119","DOI":"10.1158\/1078-0432.CCR-05-2454","article-title":"Blockage of epidermal growth factor receptor-phosphatidylinositol 3-kinase-AKT signaling increases radiosensitivity of K-RAS mutated human tumor cells in vitro by affecting DNA repair","volume":"12","author":"Toulany","year":"2006","journal-title":"Clin. Cancer Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"645","DOI":"10.1093\/jnci\/djr093","article-title":"Induction of MET by ionizing radiation and its role in radioresistance and invasive growth of cancer","volume":"103","author":"Luraghi","year":"2011","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1002\/emmm.201100176","article-title":"Oncogene addiction as a foundational rationale for targeted anti-cancer therapy: Promises and perils","volume":"3","author":"Torti","year":"2011","journal-title":"EMBO Mol. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1038\/311029a0","article-title":"Molecular cloning of a new transforming gene from a chemically transformed human cell line","volume":"311","author":"Cooper","year":"1984","journal-title":"Nature"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1038\/s41568-018-0002-y","article-title":"Known and novel roles of the MET oncogene in cancer: A coherent approach to targeted therapy","volume":"18","author":"Comoglio","year":"2018","journal-title":"Nat. Rev. Cancer"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1185","DOI":"10.1002\/1878-0261.12696","article-title":"Deciphering MET-dependent modulation of global cellular responses to DNA damage by quantitative phosphoproteomics","volume":"14","author":"Bensimon","year":"2020","journal-title":"Mol. Oncol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"550","DOI":"10.15252\/emmm.201505890","article-title":"MET inhibition overcomes radiation resistance of glioblastoma stem-like cells","volume":"8","author":"Casanova","year":"2016","journal-title":"EMBO Mol. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1038\/nm.4032","article-title":"Blocking c-Met-mediated PARP1 phosphorylation enhances anti-tumor effects of PARP inhibitors","volume":"22","author":"Du","year":"2016","journal-title":"Nat. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"8516","DOI":"10.1074\/jbc.RA118.005953","article-title":"H2O2 induces nuclear transport of the receptor tyrosine kinase c-MET in breast cancer cells via a membrane-bound retrograde trafficking mechanism","volume":"294","author":"Chen","year":"2019","journal-title":"J. Biol. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1038\/s41586-019-1186-3","article-title":"Next-generation characterization of the Cancer Cell Line Encyclopedia","volume":"569","author":"Ghandi","year":"2019","journal-title":"Nature"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"ra80","DOI":"10.1126\/scisignal.2000643","article-title":"Only a subset of Met-activated pathways are required to sustain oncogene addiction","volume":"2","author":"Bertotti","year":"2009","journal-title":"Sci. Signal."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"D955","DOI":"10.1093\/nar\/gks1111","article-title":"Genomics of Drug Sensitivity in Cancer (GDSC): A resource for therapeutic biomarker discovery in cancer cells","volume":"41","author":"Yang","year":"2013","journal-title":"Nucleic Acids Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1038\/nmeth.3853","article-title":"Growth rate inhibition metrics correct for confounders in measuring sensitivity to cancer drugs","volume":"13","author":"Hafner","year":"2016","journal-title":"Nat. Methods"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1016\/j.molonc.2012.12.007","article-title":"BRCA1\/2BRCA1\/2 mutation analysis in 41 ovarian cell lines reveals only one functionally deleterious BRCA1 mutation","volume":"7","author":"Stordal","year":"2013","journal-title":"Mol. Oncol."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Burgess, B.T., Anderson, A.M., McCorkle, J.R., Wu, J., Ueland, F.R., and Kolesar, J.M. (2020). Olaparib Combined with an ATR or Chk1 Inhibitor as a Treatment Strategy for Acquired Olaparib-Resistant. Diagnostics, 10.","DOI":"10.3390\/diagnostics10020121"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"i40","DOI":"10.1093\/annonc\/mdw094","article-title":"PARP inhibitors in ovarian cancer","volume":"27","author":"Ledermann","year":"2016","journal-title":"Ann. Oncol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1016\/j.celrep.2015.12.046","article-title":"Platinum and PARP Inhibitor Resistance Due to Overexpression of MicroRNA-622 in BRCA1-Mutant Ovarian Cancer","volume":"14","author":"Choi","year":"2016","journal-title":"Cell Rep."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1158\/1535-7163.MCT-18-1394","article-title":"Pharmacology of the ATM Inhibitor AZD0156: Potentiation of Irradiation and Olaparib Responses Preclinically","volume":"19","author":"Riches","year":"2020","journal-title":"Mol. Cancer Ther."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"4869","DOI":"10.1038\/s41388-020-1328-y","article-title":"Combined PARP and ATR inhibition potentiates genome instability and cell death in ATM-deficient cancer cells","volume":"39","author":"Lloyd","year":"2020","journal-title":"Oncogene"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1014","DOI":"10.1158\/2159-8290.CD-14-0380","article-title":"Synthetic lethality in ATM-deficient RAD50-mutant tumors underlies outlier response to cancer therapy","volume":"4","author":"Iyer","year":"2014","journal-title":"Cancer Discov."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"13701","DOI":"10.1038\/ncomms13701","article-title":"MEK inhibitors block growth of lung tumours with mutations in ataxia-telangiectasia mutated","volume":"7","author":"Smida","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2220","DOI":"10.1038\/s41467-020-15905-6","article-title":"Protein-altering germline mutations implicate novel genes related to lung cancer development","volume":"11","author":"Ji","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"6596","DOI":"10.1038\/onc.2008.280","article-title":"Atm heterozygosity does not increase tumor susceptibility to ionizing radiation alone or in a p53 heterozygous background","volume":"27","author":"Mao","year":"2008","journal-title":"Oncogene"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1083\/jcb.201204098","article-title":"Kinase-dead ATM protein causes genomic instability and early embryonic lethality in mice","volume":"198","author":"Yamamoto","year":"2012","journal-title":"J. Cell Biol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1038\/nature01368","article-title":"DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation","volume":"421","author":"Bakkenist","year":"2003","journal-title":"Nature"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"B\u00e5\u00e5th, M., J\u00f6nsson, J.M., Westbom Fremer, S., Mart\u00edn de la Fuente, L., Tran, L., Malander, S., Kannisto, P., M\u00e5sb\u00e4ck, A., Honeth, G., and Hedenfalk, I. (2021). MET Expression and Cancer Stem Cell Networks Impact Outcome in High-Grade Serous Ovarian Cancer. Genes, 12.","DOI":"10.3390\/genes12050742"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1186\/s12967-020-02613-4","article-title":"Development of a 3D functional assay and identification of biomarkers, predictive for response of high-grade serous ovarian cancer (HGSOC) patients to poly-ADP ribose polymerase inhibitors (PARPis): Targeted therapy","volume":"18","author":"Sheta","year":"2020","journal-title":"J. Transl. Med."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"11157","DOI":"10.1111\/jcmm.17037","article-title":"MET inhibition enhances PARP inhibitor efficacy in castration-resistant prostate cancer by suppressing the ATM\/ATR and PI3K\/AKT pathways","volume":"25","author":"Zhou","year":"2021","journal-title":"J. Cell. Mol. Med."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"564601","DOI":"10.3389\/fcell.2020.564601","article-title":"PARP Inhibitors: Clinical Relevance, Mechanisms of Action and Tumor Resistance","volume":"8","author":"Rose","year":"2020","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.ceb.2019.07.013","article-title":"Oriented cell divisions in epithelia: From force generation to force anisotropy by tension, shape and vertices","volume":"62","year":"2020","journal-title":"Curr. Opin. Cell Biol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1038\/sj.embor.7400046","article-title":"Cyclin B degradation leads to NuMA release from dynein\/dynactin and from spindle poles","volume":"5","author":"Gehmlich","year":"2004","journal-title":"EMBO Rep."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1815","DOI":"10.15252\/embj.201488147","article-title":"NuMA interacts with phosphoinositides and links the mitotic spindle with the plasma membrane","volume":"33","author":"Kotak","year":"2014","journal-title":"EMBO J."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"177","DOI":"10.4161\/cc.27040","article-title":"NuMA phosphorylation dictates dynein-dependent spindle positioning","volume":"13","author":"Kotak","year":"2014","journal-title":"Cell Cycle"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"2703","DOI":"10.1093\/nar\/gkz138","article-title":"The nuclear structural protein NuMA is a negative regulator of 53BP1 in DNA double-strand break repair","volume":"47","author":"Liu","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1091","DOI":"10.4161\/cc.27945","article-title":"ATM controls proper mitotic spindle structure","volume":"13","author":"Palazzo","year":"2014","journal-title":"Cell Cycle"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1007\/s10549-018-4888-6","article-title":"PARP3 inhibitors ME0328 and olaparib potentiate vinorelbine sensitization in breast cancer cell lines","volume":"172","author":"Amrein","year":"2018","journal-title":"Breast Cancer Res. Treat."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1023","DOI":"10.4161\/cc.10.7.15169","article-title":"PARP-3, a DNA-dependent PARP with emerging roles in double-strand break repair and mitotic progression","volume":"10","author":"Boehler","year":"2011","journal-title":"Cell Cycle"},{"key":"ref_52","first-page":"3510","article-title":"p145, a protein with associated tyrosine kinase activity in a human gastric carcinoma cell line","volume":"8","author":"Giordano","year":"1988","journal-title":"Mol. Cell. Biol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1242\/jcs.111.2.237","article-title":"Agonistic monoclonal antibodies against the Met receptor dissect the biological responses to HGF","volume":"111","author":"Prat","year":"1998","journal-title":"J. Cell Sci."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/10\/5770\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:16:07Z","timestamp":1760138167000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/10\/5770"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,5,21]]},"references-count":53,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2022,5]]}},"alternative-id":["ijms23105770"],"URL":"https:\/\/doi.org\/10.3390\/ijms23105770","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,5,21]]}}}