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
Jul 2026· Clinical Cancer Research· Vol 32, pp. A089-A089· 0 citations
TL;DR
An orally bioavailable prodrug of ADT-1004, 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).
Abstract
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.
Multiple cancers arise from co-occurring mutations that activate RAS/MAPK and Wnt/β-catenin signaling pathways, which cooperate to drive tumorigenesis, metastasis, and drug resistance. A dual inhibitor of RAS and β-catenin signaling may offer a more effective therapeutic strategy compared with monospecific inhibitors of RAS or β-catenin currently in clinical trials for such cancers. We previously reported that the cGMP-degrading phosphodiesterase 10A (PDE10) isozyme is overexpressed in various cancers and that pharmacological inhibition or genetic silencing of PDE10 selectively suppresses the growth of cancer cells with high PDE10 expression relative to normal cells with low PDE10 levels. Because conventional PDE10 inhibitors developed for CNS disorders are rapidly metabolized and cause sedation, we developed ADT-030, a PDE10 inhibitor optimized for systemic bioavailability. ADT-030 potently inhibited recombinant PDE10 at concentrations that bind PDE10 in cells. Similar concentrations activated cGMP-dependent PKG, phosphorylated and degraded the oncogenic pool of β-catenin, and suppressed EGF-stimulated RAS-mediated MAPK/AKT signaling, resulting in mitotic arrest and apoptosis. Notably, cancer cells that developed cross-resistance to pan-RAS, pan-KRAS, and mutant-specific KRAS inhibitors retained full sensitivity to ADT-030. Oral administration of ADT-030 demonstrated robust antitumor activity across multiple mouse tumor models (orthotopic, xenograft, PDX, and chemically induced) and cancer types. KRAS-mutant pancreatic and lung cancer models were particularly sensitive to ADT-030, resulting in tumor regression, metastasis inhibition, and durable efficacy that persisted well beyond the treatment period. ADT-030 also inhibited tumor growth in a PDX model of adrenocortical carcinoma, a cancer driven by CTNNB1 mutations. Deep immunophenotyping studies revealed a significant impact of ADT-030 treatment on the tumor immune microenvironment, characterized by selective induction of apoptosis in MDSC cells and increased tumor infiltration by CD8+ T cells and NK cells. The activity of ADT-030 was comparable to that of chemotherapy and immune checkpoint inhibitors, while combinations showed greater efficacy. These results support IND-enabling studies of ADT-030 as a monotherapy or in combination with standard-of-care treatments for patients with a broad range of RAS-driven cancers, and especially for patients who relapsed after RAS inhibitor treatment. Because PDE10 has low expression and no known physiological function outside the CNS, ADT-030 is not expected to cause on-target toxicities associated with monospecific RAS or β-catenin inhibitors.
Xi Chen, Dhana S.R. Bandi, Ganji P. Nagaraju, Junwei Wang, Sindhu Ramesh, Kristy L. Berry, Khalda Fadlalla, Elmar Nurmemmedov, Ivan Babic, Gang Zhou, Fokhrul Hossain, Suresh Kumar, Nitin Roper, Jeremy B. Foote, Donald J. Buchsbaum, Adam B. Keeton, Yulia Y. Maxuitenko, Bassel F. El-Rayes, Gary A. Piazza. ADT-030, a novel PDE10 inhibitor that blocks RAS and β-catenin signaling with robust and durable antitumor activity and potential to mitigate resistance and on-target toxicities of monospecific 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 B005.
Xi Chen, D. Bandi, G. P. Nagaraju et al.· Clinical Cancer Research· 0 citations
This review systematically summarizes the molecular mechanisms driving KRAS G12C‑mutant lung cancer, clinical applications of targeted drugs, resistance and heterogeneity challenges, and progress in combination therapy, providing a reference for clinical decision-making and further research in this field.
Xizhi Zha· Theoretical and Natural Scie...· 0 citations
This review summarizes recent progress in KRAS G12D-targeted inhibitors and degraders, highlighting current challenges and future opportunities for improving KRAS-directed cancer treatment.
Platinum-based chemotherapy remains one of the standard treatments for advanced non-small cell lung cancer (NSCLC); however, most patients eventually relapse because of acquired resistance. A major driver of therapeutic resistance is hyperactivation of the DNA damage response (DDR), which allows tumor cells to repair chemotherapy-induced DNA lesions and evade cytotoxic stress. The deubiquitinating enzyme USP10 stabilizes multiple DDR and pro-survival proteins, making it an attractive therapeutic target for re-sensitizing resistant tumors. Inhibition of USP10 may impair DNA repair signaling and enhance anti-tumor activity in resistant NSCLC models. We developed selective and potent USP10 inhibitors through medicinal chemistry optimization. GL-458 was identified as the lead USP10 inhibitor and demonstrated improved selectivity in deubiquitinase (DUB) assays compared with previously reported USP10 inhibitors, including Wu-5 and P22077. P22077 functions as a covalent, non-specific inhibitor, whereas Wu-5 is a non-covalent, non-selective inhibitor. In cellular viability MTT assays, GL-458 demonstrated greater potency, with approximately 3-fold lower IC50 values than Wu-5 and approximately 1.7-fold lower IC50 values than P22077. GL-458 target selectivity and target-dependent cytotoxicity were further evaluated using mouse KRAS/TP53-driven (KP) and USP10-knockout KPU NSCLC models. MTT and colony formation assays demonstrated robust, dose-dependent suppression of proliferation and clonogenic survival. Combination treatment studies using CellTiter-Glo showed that GL-458 effectively re-sensitized cisplatin-resistant cells. Flow cytometric analysis using the Click-iT EdU assay demonstrated early G0/G1 cell-cycle arrest accompanied by ATM/ATR activation, increased gamma-H2AX, and elevated cleaved PARP-1 expression. Immunofluorescence analyses revealed accumulation of gamma-H2AX, 53BP1, and Chk1 foci, consistent with impaired DNA repair capacity. Co-treatment with ATM inhibitors further validated the involvement of DDR signaling in mediating the anti-tumor effects of USP10 inhibition. Generative AI tools were used solely for language editing and improvement of abstract clarity; all scientific content, data interpretation, and conclusions were generated and verified by the authors.
Sadaf Dorandish, Komal Bhayekar, Amirreza Samarbakhsh, Babita Kushwaha. Dorandish, Yubin Ge, Navnath S Gavande. Selective USP10 inhibition by GL-458 re-sensitizes platinum-resistant non-small cell lung cancer through DNA damage response disruption [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 A062.
Sadaf Dorandish, Komal Bhayekar, Amirreza Samarbakhsh et al.· Clinical Cancer Research· 0 citations
Checkpoint kinase 1 (CHK1), a master regulator of replication stress, has been investigated as a potential therapeutic target for over two decades. More recently, CHK1 has been implicated as a target for the treatment of ecDNA-driven, oncogene-amplified cancers. However, clinical-stage CHK1 inhibitors have historically faced challenges related to dosing schedule, tolerability, and clinical efficacy, although recent studies suggest that biomarker-driven approaches and alternative dosing strategies may address some of these limitations. Structure-guided optimization led to the discovery of BBI-355, a potent, selective, and orally available CHK1 inhibitor. BBI-355 demonstrates strong antitumor activity when dosed orally in mouse xenograft models, achieving regressions both as a single agent and in combination with targeted therapies. BBI-355 also displays favorable ADMET and PK properties and has been advanced to a clinical trial for patients with oncogene amplified cancers.
S. Meyer, Sudhir Chowdhry, Rachelle Elsdon et al.· Journal of Medicinal Chemist...· 0 citations
RAS alterations mediate resistance to targeted agents in approximately 10% of oncogene-driven lung cancer, and Rational combinations with novel RAS inhibitors are effective in preclinical models, providing the basis for their clinical investigation and extending the paradigm of precision oncology.
F. Facchinetti, L. Friboulet, L. Liao et al.· Annals of Oncology· 0 citations
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