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We have shown that a unique <jats:italic>E. coli<\/jats:italic> MazF-MazE toxin\u2013antitoxin (TA) system can be used for selective and effective eradication of <jats:italic>RAS<\/jats:italic>-mutated cancer cells. This out of the box strategy holds great promise for effective cancer treatment and management. We provide proof of concept for a novel platform to selectively eradicate cancer cells using an adenoviral delivery system based on the adjusted natural bacterial system. We generated adenoviral vectors carrying the mazF toxin (pAdEasy-Py4-SV40mP-mCherry-MazF) and the antitoxin mazE (pAdEasy-RGC-SV40mP-MazE-IRES-GFP) under the regulation of <jats:italic>RAS<\/jats:italic> and <jats:italic>p53<\/jats:italic>, resp. The control vector carries the toxin without the RAS-responsive element (pAdEasy-\u0394Py4-SV40mP-mCherry-MazF). In vitro, the mazF-mazE TA system (Py4-SV40mP-mCherry-MazF+RGC-SV40mP-MazE-IRES-GFP) induced massive, dose-dependent cell death, at 69% compared to 19% for the control vector, in a co-infected HCT116 cell line. In vivo, the system caused significant tumor growth inhibition of HCT116 (<jats:italic>KRAS<\/jats:italic><jats:sup><jats:italic>mut<\/jats:italic><\/jats:sup><jats:italic>\/p53<\/jats:italic><jats:sup><jats:italic>mut<\/jats:italic><\/jats:sup>) tumors at 73 and 65% compared to PBS and \u0394PY4 control groups, resp. In addition, we demonstrate 65% tumor growth inhibition in HCT116 (<jats:italic>KRAS<\/jats:italic><jats:sup><jats:italic>mut<\/jats:italic><\/jats:sup><jats:italic>\/p53<\/jats:italic><jats:sup><jats:italic>wt<\/jats:italic><\/jats:sup>) cells, compared to the other two control groups, indicating a contribution of the antitoxin in blocking system leakage in WT RAS cells. These data provide evidence of the feasibility of using mutations in the <jats:italic>p53<\/jats:italic> and <jats:italic>RAS<\/jats:italic> pathway to efficiently kill cancer cells. The platform, through its combination of the antitoxin (mazE) with the toxin (mazF), provides effective protection of normal cells from basal low activity or leakage of mazF.<\/jats:p>","DOI":"10.1038\/s41388-021-01792-8","type":"journal-article","created":{"date-parts":[[2021,6,25]],"date-time":"2021-06-25T11:02:53Z","timestamp":1624618973000},"page":"4967-4979","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Innovative dual system approach for selective eradication of cancer cells using viral-based delivery of natural bacterial toxin\u2013antitoxin system"],"prefix":"10.1038","volume":"40","author":[{"given":"Shiran","family":"Shapira","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ilana","family":"Boustanai","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dina","family":"Kazanov","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marina","family":"Ben Shimon","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ahmad","family":"Fokra","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5283-6991","authenticated-orcid":false,"given":"Nadir","family":"Arber","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2021,6,25]]},"reference":[{"key":"1792_CR1","doi-asserted-by":"publisher","first-page":"646","DOI":"10.1016\/j.cell.2011.02.013","volume":"144","author":"D Hanahan","year":"2011","unstructured":"Hanahan D, Weinberg RA. 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