Biology subjects

Maxuitenko, Y.

Publications and source records attributed to Maxuitenko, Y..

2 recordsLinked to original sources

bioRxiv2026

Targeting phosphodiesterase 10A disrupts MAPK signaling pathways in the tumor microenvironment to unleash antitumor immunity

Phosphodiesterase 10A (PDE10A), a cyclic nucleotide-degrading enzyme, is overexpressed in various human cancers. While PDE10A inhibition using small-molecule inhibitors or gene silencing suppresses tumor growth in xenograft models, its precise mechanism of action and immunological impact remain unclear. Here, we report that ADT-030, a novel PDE10A inhibitor, exhibits potent cytotoxicity against a broad range of murine tumor cell lines. ADT-030 is orally bioavailable and effectively suppresses tumor growth across multiple syngeneic mouse models. Notably, its efficacy is diminished in immunodeficient mice or upon CD8+ T cell depletion, highlighting a critical dependence on host immunity. The immunostimulatory properties of ADT-030 are further supported by its ability to induce immunogenic tumor cell death and promote dendritic cell (DC) maturation, its reliance on Batf3-expressing DCs to elicit antitumor CD8+ T cell response, and its synergy with anti-PD-1 therapy. Comprehensive immune profiling in the 4T1 breast cancer model, both in orthotopic and metastatic settings, revealed that ADT-030 selectively reduces myeloid-derived suppressor cells (MDSCs) while normalizing the immune landscape within the tumor. Mechanistically, ADT-030 disrupts multiple components of the mitogen-activated protein kinase (MAPK) signaling network in both tumor cells and MDSCs, leading to induction of apoptosis in these populations. These findings highlight the multi-faceted impact of PDE10A inhibition as a therapeutic strategy that not only disrupts tumor-intrinsic oncogenic signaling to inhibit tumor progression but also reshapes the tumor immune microenvironment to unleash antitumor immunity.

immunology↗

bioRxiv2023

Novel Pan-RAS Inhibitor ADT-007 Induces Tumor Regression in Mouse Models of GI Cancer

Here, we describe a novel pan-RAS inhibitor, ADT-007, that potently inhibited the growth of RAS mutant cancer cells irrespective of the RAS mutation or isozyme. RASWT cancer cells with GTP-activated RAS from upstream mutations were equally sensitive. Conversely, RASWT cancer cells harboring downstream BRAF mutations and normal cells were essentially insensitive to ADT-007. Sensitivity of cancer cells to ADT-007 required activated RAS and dependence on RAS for proliferation, while insensitivity was attributed to metabolic deactivation by UDP-glucuronosyltransferases expressed in RASWT and normal cells but repressed in RAS mutant cancer cells. ADT-007 binds nucleotide-free RAS to block GTP activation of effector interactions and MAPK/AKT signaling, resulting in mitotic arrest and apoptosis. ADT-007 displayed unique advantages over mutant-specific KRAS and pan-KRAS inhibitors, as well as other pan-RAS inhibitors that could impact in vivo antitumor efficacy by escaping compensatory mechanisms leading to resistance. Local administration of ADT-007 showed robust antitumor activity in syngeneic immune-competent and xenogeneic immune-deficient mouse models of colorectal and pancreatic cancer. The antitumor activity of ADT-007 was associated with the suppression of MAPK signaling and activation of innate and adaptive immunity in the tumor immune microenvironment. Oral administration of ADT-007 prodrug also inhibited tumor growth, supporting further development of this novel class of pan-RAS inhibitors for RAS-driven cancers. SIGNIFICANCEADT-007 has unique pharmacological properties with distinct advantages over other RAS inhibitors by circumventing resistance and activating antitumor immunity. ADT-007 prodrugs and analogs with oral bioavailability warrant further development for RAS-driven cancers.

cancer biology↗