Abstract 4140: Oncogenic KRAS inhibition with ADT-007 primes T cell responses in pancreatic ductal adenocarcinoma
Authors: Foote Jeremy B. , Mattox Tyler E. , Keeton Adam B. , Purnachandra Ganji N. , Maxuitenko Yulia , Chen Xi , Valiyaveettil Jacob , Buchsbaum Donald J. , Piazza Gary A. , El-Rayes Bassel F. 
Published: April 2023

Background: Pancreatic ductal adenocarcinoma (PDAC) has low (&lt;11%) 5-year survival due to the presence of advanced disease at diagnosis. Currently standard of care provides a median survival of 1 year in the majority of patients presenting with advanced disease. Targeting oncogenic KRAS, which is mutated in &gt;90% of human PDAC tumors, provides an opportunity to inhibit a critical pathway and significantly impact standard of care in patients diagnosed with PDAC. Furthermore, evidence indicates that inhibiting-oncogenic KRAS signaling modulates anti-tumor immune responses and demonstrates synergy with immune checkpoint blockade in pre-clinical models. The purpose of this study is to evaluate efficacy and impact on anti-tumor immunity of a novel inhibitor, ADT-007 that demonstrates pan-RAS inhibitory activity.

Methods: Female C57BL/6J, C57BL/6J. Ifng/Thy1.1 KI;Cg-Tg-IL2tm1/eGFP/Weav (IFNg-Thy1.1/IL-2-GFP reporter mice), or immune deficient (T/B cells) Rag 1 −/− mice (n=5-10/group) were implanted SQ with 106 mouse derived PDAC cell lines (7160c2 and 2838c3) bearing KRASG12D mutation, and then randomized (day 7), into vehicle (5% DMSO/5% Kolliphor/90% H2O) or ADT-007 treatment, which was administered SQ (peritumoral), BID at 5 mg/kg for 2 - 3 weeks. Tumor growth in vitro (IC50), KRAS-MAPK/AKT signaling, in vivo tumor volumes (tv = L x W2/2), and tumor immune responses were assessed by CellTiter Glo, phosphoflow/western blotting, bi-weekly caliper measurements, and multi-parameter flow cytometry, respectively.

Results: ADT-007 inhibited KRAS-MAPK/AKT signaling in human and mouse PDAC cell lines inducing G2-M phase arrest and apoptosis at low nanomolar concentrations. Peritumoral administration of ADT-007 inhibited tumor cell growth in vivo, modulating T cells in the tumor microenvironment (TME), specifically, an increase in tumor infiltrating, CD44+ CD62L− CD4+ and CD8+ T cells and increases in production of TNFα, IFN-γ, IL-2, and granzyme B upon stimulation with PMA/ionomycin.

Conclusion: The small molecule inhibitor, ADT-007 blocks oncogenic KRAS signaling and modulates T cell activation and function in the TiME of immune competent, syngeneic mouse models of PDAC. More broadly, these findings indicate that a pan-RAS inhibitor is capable of modulating anti-tumor immune responses extending previous observations that targeted inhibition of oncogenic KRASG12C modulates tumor immunity in animal models of colon and lung cancer.

Citation Format: Jeremy B. Foote, Tyler E. Mattox, Adam B. Keeton, Ganji N. Purnachandra, Yulia Maxuitenko, Xi Chen, Jacob Valiyaveettil, Donald J. Buchsbaum, Gary A. Piazza, Bassel F. El-Rayes. Oncogenic KRAS inhibition with ADT-007 primes T cell responses in pancreatic ductal adenocarcinoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4140.