KRAS G12

P3, N=614, Not yet recruiting, Astellas Pharma Global Development, Inc.

P2, N=40, Recruiting, Zhejiang University | Not yet recruiting --> Recruiting | Initiation date: Nov 2025 --> Feb 2026

Mechanistically, XMU-MP-9 acts as a bifunctional compound to bind the C2 domain of NEDD4-1 and an allosteric site of K-RAS to enhance NEDD4-1 and K-RAS interaction, and to induce a conformational change of NEDD4-1/K-RAS complex to allow NEDD4-1 targeting K128 of K-RAS for ubiquitination. Hence, our study presents an effective way to degrade K-RAS mutants to prevent tumor development.

Structural studies of the D92C variant in complex with the compound BI-1830 uncovered a distinct novel binding pocket, highlighting the inherent plasticity of the region between switch-II and α3, that can accommodate diverse chemical entities in various conformations. This method holds significant potential for advancing drug discovery efforts against elusive targets such as oncogenic RAS mutants.

P1, N=498, Active, not recruiting, Genentech, Inc. | Trial completion date: Sep 2026 --> Dec 2027 | Trial primary completion date: Sep 2026 --> Dec 2027

Indeed, we found KPA cells were more sensitive to hydrogen peroxide and diethyl maleate-induced oxidative stress as compared to KP and KPS cells. Together, these results demonstrate that PIK3CA is not required for lung cancer cell growth induced by mutant KRAS in vitro but is critically needed for in vivo progression and growth.

Reflex NGS at diagnosis in resected Stage 0-IA LUAD is feasible, rapid, and reveals a high rate of actionable alterations, which may support its integration in the future into early-stage diagnostic workflows.

Rational combination strategies that pair genomic-targeted agents (sotorasib and adagrasib) with metabolic inhibitors (CB-839 and TVB-2640) show promise in overcoming adaptive resistance. Integrating genomic and metabolic profiling may enhance precision oncology approaches and improve clinical outcomes.

Historically considered "undruggable," KRAS has recently become a viable therapeutic target with the development of selective KRAS G12C inhibitors such as sotorasib (AMG510) and adagrasib (MRTX849). We discuss the mechanisms of intrinsic and acquired resistance, current monotherapy limitations, and the rationale for combination strategies aimed at overcoming resistance. Additionally, we explore future therapeutic perspectives, including novel inhibitors, combination regimens, and emerging precision medicine approaches, to optimize treatment outcomes for patients with KRAS G12C-mutant NSCLC.

TCR3-T cells showed significantly optimized avidity and response to tumor cell lines, retained specificity for the KRAS G12V8-16 peptide with no response to normal cells, killed tumor cells that highly expressed programmed cell death-ligand 1 in vitro and in vivo, proliferated without being seriously affected by indoleamine 2,3-dioxygenase, resisted transforming growth factor β, and infiltrated and recruited other immune cells to the tumor site through chemokines. TCR3 may be useful for KRAS neoantigen-targeted clinical immunotherapy, help resolve cancer immune escape, and enhance clinical effectiveness and safety.

In this phase I study, we test a pooled synthetic long peptide vaccine targeting the six KRAS mutations (G12V, G12A, G12R, G12C, G12D, G13D) with ipilimumab and nivolumab in resected pancreatic adenocarcinoma. The vaccine also generates cross-reactive T cells that recognize more than one mutant KRAS antigen. These findings support the safety and diverse anti-tumor immunity of mutant KRAS vaccines (NCT04117087).

PDIA6, driven by KRASG12D, alleviates ICD and promotes immune evasion, functioning as a predictive biomarker to screen ICB-sensitive patients and a therapeutic target to improve ICB efficacy in PDAC with KRAS mutations.