First in class hSSB2 activator as a dual therapeutic strategy for overcoming RAS/MAPK inhibitor resistance while protecting normal epithelia in aggressive cancers

BCN077 is a first-in-class small-molecule activator of the human single-stranded DNA binding complex hSSB2/1, a key regulator of replication stress responses and DNA repair. In cancer cells with high baseline replication stress and defective cell-cycle checkpoints, pharmacologic activation of hSSB2/1 by BCN077 drives excessive replication fork processing and accumulation of unrepaired double-strand breaks, forcing damaged cells through mitosis and triggering mitotic catastrophe. In contrast, normal stem and progenitor cells with intact checkpoints use hSSB2/1 activation to pause, repair therapy-induced DNA damage more efficiently, and survive, creating a therapeutically favorable differential between tumor killing and normal tissue protection. This dual mechanism positions BCN077 represents a novel DNA damage-response drug class that couples synthetic lethality in genomically unstable tumors with concurrent radio/chemo-protection of normal tissues. In a BRAFV600E colorectal cancer model using RKO xenografts in male athymic BALB/c nu/nu mice, we are evaluating the novel agent BCN077 in both naïve and treatment-resistant settings. RKO typically exhibits immunosuppressive microenvironments with reduced T-cell presence and high myeloid-derived suppressor cell activity. Mice were randomized to four arms: vehicle control, BCN077 monotherapy, standard FOLFOX plus Encorafenib (Braftovi®) and cetuximab, or the same triplet regimen combined with BCN077. Further we have evaluated the effect of BCN077 with respect to method of cell death confirming mitotic catastrophe as the form of cell death not only in RKO but also Panc-1 and other cancer cell lines showing positive Histone H-3, gamma H2AX stain, comet assay Bub1 and MAD1 staining among other key biomarkers. The NCI-60 panel also was conducted across cancer types showing effectiveness across cancer types with growth inhibition (GI50), Lethal concentration (LC50) and total growth inhibition (TGI) data. The normal cell line HEK293 did not show positive under the same conditions having intact cell cycle checkpoint control. Lastly, in vivo data clearly indicate that BCN077 has profound protective effects from cytotoxic therapy employed in cancer treatment such as radiation. hSSB2 is a novel target and holds great promise for use in cancer therapy, in particular where there is resistance to targeted therapeutics in the MAPK pathway such as RAS, BRAF, MEK inhibitors where resistance enables cell cycle checkpoint evasion.