Progress and challenges in the design and development of selective KRAS G12D-targeted drug discovery: inhibitors, degraders and emerging therapeutic strategies.

Targeting KRAS in Cancer: Advances in Precision Oncology and Drug Development

These breakthroughs have validated direct KRAS inhibition as an effective therapeutic strategy, however, durable clinical responses remain limited by intrinsic and acquired resistance, pathway reactivation, tumour heterogeneity, and the lack of effective therapies for non-G12C KRAS mutations.

Expanding Addressable KRAS Mutations through the Structure- and Property-Based Design of Dual-State (GDP/GTP), Reversible Pan-KRAS Inhibitors

Therapeutically targeting mutant KRAS represents a clinically validated approach for the treatment of solid tumors, including lung, colon, and pancreatic cancers. The approval of covalent KRASG12C inhibitors, such as sotorasib and adagrasib, has fueled intense interest in expanding KRAS-directed therapies to mutations beyond KRAS G12C, such as KRAS G12D, KRAS G12V, and KRAS G13D. Here, we describe the structure- and property-based design of reversible inhibitors of diverse oncogenic mutants of KRAS, leading to AM-2383, a pan-KRAS inhibitor that blocks signaling via both the GDP(off)- and GTP(on)-bound states of KRAS, while sparing the closely related RAS isoforms HRAS and NRAS. AM-2383 disrupts signaling downstream of KRAS, potently suppressing the growth of KRAS G12D and KRAS G12V tumor xenografts following oral administration. AM-2383 represents an important proof-of-concept that structural insights from prior covalent KRASG12C inhibitors can be leveraged in the design of efficacious and well-tolerated inhibitors of diverse KRAS mutations.

KRAS-mutated Non-Small Cell Lung Cancer: Drugging the Undruggable.

KRAS driver mutations have classically been considered undruggable by direct inhibitors in non-small cell lung cancer (NSCLC) as well as other solid tumors. However, recent advances have led to the first successful direct KRAS inhibitors, beginning with the development of KRASG12C inhibitors targeting the inactive GDP-bound state of KRAS. These initial KRASG12C (OFF) inhibitors demonstrated real but modest activity in KRASG12C-mutated mNSCLC. The development of more potent optimized KRASG12C (OFF) inhibitors has sought to improve upon the clinical activity of the initial raft of KRASG12C (OFF) inhibitors. Combination therapy with PD-1 inhibitors, as well as other classes of drugs, is also under intense investigation in NSCLC and other solid tumors. Nevertheless, primary and acquired resistance, as well as a variable and peculiar tendency to autoimmune hepatitis, have complicated efforts to develop this class of inhibitors in KRASG12C-mutated mNSCLC. In parallel, new direct inhibitor classes have emerged recently, including tri-complex ON-state inhibitors and dual-state ON/OFF inhibitors capable of targeting not only KRASG12C but also other KRAS mutations, as well as panKRAS and panRAS strategies. These agents have the potential to broaden the activity of initial KRASG12C (OFF) inhibitors and to avoid certain mechanisms of resistance and toxicity, but remain early in development with limited data. The KRAS therapeutic landscape is evolving rapidly, with many promising competing strategies each seeking to distinguish itself in an increasingly crowded therapeutic landscape.

KRAS G12C-Targeted Therapy Strategy for Lung Cancer: Mechanism, Clinical Practice and Challenges

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.

KRAS-Targeted Therapies in NSCLC: Resistance, Combination Strategies, and Emerging Clinical Paradigms

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.