Research Papers:

Transformation of immunosuppressive mtKRAS tumors into immunostimulatory tumors by Nerofe and Doxorubicin

Joel Ohana, Uziel Sandler, Orly Devary and Yoram Devary _

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Oncotarget. 2023; 14:688-699. https://doi.org/10.18632/oncotarget.28467

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Joel Ohana1, Uziel Sandler1,2, Orly Devary1 and Yoram Devary1

1 Immune System Key (ISK) Ltd., Jerusalem 9746009, Israel

2 Department of Bio-Informatics, Lev Academic Center (JCT), Jerusalem 91160, Israel

Correspondence to:

Yoram Devary, email: [email protected]

Keywords: Colorectal cancer; KRAS; apoptosis; hormone peptide; endoplasmic reticulum stress

Received: March 29, 2023     Accepted: June 15, 2023     Published: July 01, 2023

Copyright: © 2023 Ohana et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Members of the rat sarcoma viral oncogene (RAS) subfamily KRAS are frequently mutated oncogenes in human cancers and have been identified in pancreatic ductal, colorectal, and lung adenocarcinomas. In this study, we show that a derivative of the hormone peptide Tumor Cell Apoptosis Factor (TCApF), Nerofe (dTCApFs), in combination with Doxorubicin (DOX) substantially reduces viability of tumor cells. It was observed that the combination of Nerofe and DOX downregulated KRAS signaling via miR217 upregulation, resulting in enhanced apoptosis of tumor cells. In addition, the combination of Nerofe and DOX also resulted in activation of the immune system against tumor cells, manifested by an increase in the immunostimulatory cytokines IL-2 and IFN-γ as well as the recruitment of NK cells and M1 macrophages to the tumor site.

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