ADT-1004: A First-in-Class, Orally Bioavailable Selective pan-RAS Inhibitor for Pancreatic Ductal Adenocarcinoma

Abstract

Here, we evaluated in vivo antitumor activity, target engagement, selectivity, and tumor specificity of ADT-1004, an orally bioavailable prodrug of ADT-007 having highly potent and selective pan-RAS inhibitory activity. ADT-1004 strongly blocked tumor growth and RAS activation in mouse PDAC models without discernable toxicity. As evidence of target engagement and tumor specificity, ADT-1004 inhibited activated RAS and ERK phosphorylation in PDAC tumors at dosages approximately 10-fold below the maximum tolerated dose and without discernable toxicity. ADT-1004 inhibited ERK phosphorylation in PDAC tumors. In addition, ADT-1004 blocked tumor growth and ERK phosphorylation in PDX PDAC models with KRAS ^G12D , KRAS ^G12V , KRAS ^G12C , or KRAS ^G13Q mutations. ADT-1004 treatment increased CD4 ⁺ and CD8 ⁺ T cells in the TME consistent with exhaustion and increased MHCII ⁺ M1 macrophage and dendritic cells. ADT-1004 demonstrated superior efficacy over sotorasib and adagrasib in tumor models involving human PDAC cells resistant to these KRAS ^G12C inhibitors. As evidence of selectivity for tumors from PDAC cells with mutant KRAS, ADT-1004 did not impact the growth of tumors from RAS ^WT PDAC cells. Displaying broad antitumor activity in multiple mouse models of PDAC, along with target engagement and selectivity at dosages that were well tolerated, ADT-1004 warrants further development.

Significance: ADT-1004 displayed robust antitumor activity in aggressive and clinically relevant PDAC models with unique tumor specificity to block RAS activation and MAPK signaling in RAS mutant cells. As a pan-RAS inhibitor, ADT-1004 has broad activity and potential efficacy advantages over allele-specific KRAS inhibitors by averting resistance. These findings support clinical trials of ADT-1004 for KRAS mutant PDAC.