Ivan Babic

Targeting the NuRD Component, CHD4, Impairs Foxp3+ Treg Cell Production and Function and Promotes Anti-Tumor Immunity

Little is known about why Foxp3⁺ regulatory T (Treg) cells require at least three HDAC1/HDAC2-containing chromatin-remodeling complexes (NuRD, Sin3 and CoREST), or whether selective disruption of these complexes can be exploited to enhance antitumor immunity. Here, we investigated the role of chromodomain helicase DNA- binding protein 4 (CHD4), the ATP-dependent remodeling subunit of the NuRD complex, in Treg biology. Conditional deletion of Chd4 in Foxp3⁺ Tregs resulted in severe systemic autoimmunity and early lethality, accompanied by reduced Foxp3 expression, impaired Treg suppressive function, and loss of Treg lineage stability. Transcriptomic analyses demonstrated that CHD4 deficiency closely phenocopied Hdac2 deletion, whereas quantitative proteomic analyses revealed that CHD4 assembles into highly conserved NuRD complexes in both Treg and conventional CD4⁺ T cells. These findings indicate that the selective dependence of Tregs on CHD4 does not arise from the formation of lineage-specific protein complexes but rather from the unique epigenetic program maintained by CHD4-containing chromatin-remodeling complexes that is required for Treg differentiation and stability. Using a novel cellular target-engagement platform, we identified CH41, a potent small-molecule inhibitor of CHD4 that recapitulated the effects of genetic CHD4 ablation on Treg function. Pharmacological inhibition of CHD4 impaired intratumoral Treg accumulation and function and significantly inhibited the growth of lung and hepatocellular carcinomas in immunocompetent, but not immunodeficient, mice, without inducing systemic autoimmunity. Collectively, our findings identify CHD4 as a critical epigenetic regulator of Treg lineage stability and establish pharmacological targeting of the CHD4/NuRD axis as a promising strategy to selectively disrupt tumor-associated Tregs and enhance antitumor immunity.

Abstract A089: ADT-1004: A mechanistically distinct pan-RAS inhibitor with the potential to escape resistance and mitigate on-target toxicities that limit efficacy and safety of other RAS inhibitors

Gain-of-function mutations in RAS genes are the most prevalent oncogenic mutations responsible for about one-third of all human malignancies. Despite decades of research, direct targeting of RAS remains a major clinical challenge, as FDA-approved RAS inhibitors and those in clinical trials have limited efficacy and on-target toxicities. We recently characterized a mechanistically distinct pan-RAS inhibitor, ADT-007, with highly potent and selective growth-inhibitory activity against cancer cells with mutant or activated RAS (Cancer Res, 2025). Cellular, biochemical, and biophysical studies demonstrated that ADT-007 binds nucleotide-free RAS, blocking GTP loading and RAS activation, leading to mitotic arrest and apoptosis. Notably, ADT-007 induced apoptosis and caused near-complete inhibition of colony formation in KRAS mutant pancreatic cancer cells, whereas the pan-KRAS inhibitor, BI-2865, and the pan-RAS inhibitor, RMC-6236, did not induce apoptosis and marginally inhibited colony formation when tested under the same conditions at 10x growth IC50 values. In addition, KRAS mutant cancer cell lines did not develop resistance to ADT-007 under chronic exposure, in contrast to BI-2865 and RMC-6236, which readily produced cultures that were essentially unresponsive to the inhibitor that induced resistance. Interestingly, the RMC-6236-resistant cells exhibited cross-resistance to BI-2865 and vice versa, as well as cross-resistance to allele-specific KRAS inhibitors, but not to ADT-007. The RAS selectivity of ADT-007 involves a unique metabolic mechanism of deactivation by UDP-glucuronosyltransferases (UGTs), which are expressed in normal cells but not in KRAS-mutant cancer cells. An orally bioavailable prodrug of ADT-007, ADT-1004, demonstrated favorable tolerability and suppressed tumor growth in orthotopic and patient-derived xenograft models of pancreatic cancer, accompanied by reductions in activated RAS and p-ERK levels (Mol Cancer, 2025). ADT-1004 displayed superior efficacy compared with sotorasib or adagrasib in a xenograft model using a resistant pancreatic cancer cell line. These findings support the further development of ADT-1004, which holds promise for broad and durable efficacy against RAS-driven cancers, with the potential to overcome resistance and on-target toxicities. Junwei Wang, Xi Chen, Bandi D. S. Reddy, Ganji P. Nagaraju, Sindhu Ramesh, Austin Moore, Thomas Holmes, Kristy L. Berry, Khalda Fadlalla, Elmar Nurmemmedov, Ivan Babic, Jeremy B. Foote, Donald J. Buchsbaum, Asfar S. Azmi, Yulia Y. Maxuitenko, Adam B. Keeton, Bassel F. El-Rayes, Gary A. Piazza. ADT-1004: A mechanistically distinct pan-RAS inhibitor with the potential to escape resistance and mitigate on-target toxicities that limit efficacy and safety of other RAS inhibitors [abstract]. In: Proceedings of AACR Drug Discovery and Development (AACR D3) Conference; 2026 Jul 21-24; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(14_Suppl):Abstract nr A089.

Abbapolin inhibitors of the PLK1 PBD as Prostate Cancer Therapeutics, in vivo activity and synergy with androgen therapy