MYC inhibition by Omomyc as a therapeutic strategy for (KRAS-mutated) colorectal cancer

Background: Colorectal cancer (CRC) is the 4th leading cause of cancer-related deaths and is in dire need of new therapeutics. Deregulation of MYC function, a proto-oncogene involved in tumorigenesis, is a feature common to most malignancies including CRC. However, no MYC inhibitor has obtained clinical approval yet. In this study, we pre-clinically validated in CRC the efficacy of Omomyc mini-protein, a MYC inhibitor developed by Dr. Soucek (Principal Investigator), which is currently in Phase I/IIa clinical trial. Importantly, as KRAS-mutated CRC (∼45% of CRC cases) is resistant to anti-EGFR therapy, the first line treatment for CRC, we investigated if Omomyc (and MYC inhibition by extension) could serve as a potential therapeutic agent for KRAS-mutated CRC. Materials and methods: We investigated the efficacy of Omomyc in both in vitro and in vivo preclinical CRC models. We made use of a panel of commercially available CRC cell lines bearing wild-type or mutated KRAS gene for in vitro assays investigating the effect of Omomyc on their proliferation as well as cell cycle. Additionally, to compare the efficacy of Omomyc in KRAS-mutated vs -wild-type background in the same cellular context, we made use of isogenic cell lines that are wild-type or mutated for KRAS. We then tested the efficacy of intravenous-administered Omomyc in vivo using KRAS-mutated cell line-derived xenograft (CDX) and patient-.derived xenograft (PDX) subcutaneous mouse models. Results: We observed that, in the in vitro setting, Omomyc significantly impeded cell growth across the panel of KRAS-mutated and -wild-type cell lines. Furthermore, we observed that the presence of KRAS mutations did not affect the efficacy of Omomyc, which caused perturbations in the cycle across the cell line panel, irrespective of their KRAS mutational status. Finally, in the in vivo models, we observed that Omomyc, administered intravenously once a week for the duration of the experiment, resulted in significantly reduced relative tumour volume at end point in both CDX and PDX CRC models. Conclusions: Our data suggest that MYC inhibition by Omomyc is a promising potential strategy for the treatment of CRC, especially but not limited to KRAS-mutated cases, hence paving the way for its clinical development as a therapeutic for CRC. Conflict of interest: Other Substantive Relationships: S. Martínez-Martín reports personal fees from Peptomyc S.L. during the conduct of the study personal fees from Peptomyc S.L. outside the submitted work. S. López-Estévez reports personal fees from Peptomyc SL during the conduct of the study personal fees from Peptomyc S.L. outside the submitted work. L. Foradada reports personal fees from Peptomyc S.L. during the conduct of the study personal fees from Peptomyc S.L. outside the submitted work. V. Castillo Cano reports other from Peptomyc S.L outside the submitted work. S. Casacuberta-Serra reports personal fees from Peptomyc S.L. during the conduct of the study personal fees from Peptomyc S.L. outside the submitted work in addition, S. Casacuberta-Serra has a patent to EP19382194 pending. M.F. Zacarias Fluck reports other from Peptomyc S.L. outside the submitted work. M. Beaulieu is a cofounder and shareholder of Peptomyc, a company focused on developing Myc inhibitors for cancer treatment. J.R. Whitfield reports Shareholder in Peptomyc. Soucek reports personal fees from Peptomyc S.L. personal fees from Peptomyc S.L. outside the submitted work in addition, L. Soucek has a patent to EP13382167.8 issued.