KRAS G12D

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

Notably, the combination of LPM5140276 and RMC4550 synergistically suppressed ERK and SHP2 phosphorylation, enhanced G0/G1 arrest and apoptosis, and improved the antitumor efficacy. Thus, LPM5140276 is a promising KRASG12D inhibitor, whose combination with SHP2 inhibition represents a viable strategy for overcoming resistance.

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.

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.

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.

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).

Trogocytosis-related CLDN18.2 inhibited the glucose uptake, glycolysis and cytotoxicity of tumour-infiltrating CD8+ T cells by promoting the ubiquitin-proteasomal degradation of β-catenin in PDAC. Therefore, targeting trogocytosis-related CLDN18.2+CD8+ T cells may be a promising therapeutic strategy to inhibit PDAC progression.

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.

For patients receiving cytarabine-based front-line chemotherapy, those with RAS mutations had shorter median OS compared to RAS-wild-type AML (27.1 vs. 122.2 months, p < 0.001)...Although 80 (66.1%) of 121 total RAS mutations were found in codons G12 or G13, most substitutions were G12D or G13D, which are not targetable by commercial RASG12C inhibitors. This study sheds light on prognostic implications of RAS mutations and may inform extension of the therapeutic reach of RAS inhibitors to AML.

Collectively, our findings reveal that the USP20-RAB8A-GLUT1 axis regulates glucose uptake and metabolic reprogramming in PDAC, thereby inhibiting tumor growth and metastasis. Targeting this signaling axis provides a novel insight into metabolic therapy for pancreatic cancer.

Methods We performed whole exome sequencing (WES), bulk RNAseq, multiplex immunofluorescence (mIF) and chromogenic immunohistochemistry (IHC) on tumor tissue and flow cytometry of the peripheral blood to study longitudinal changes following the combination of avelumab with utomilumab (a 4-1BB agonist) (arm A), PF-04518600 (an OX40 agonist) (arm B), utomilumab and PF-04518600 (arm C) and utomilumab and radiotherapy (arm D) in phase I/II study (NCT03217747). Conclusions Our findings, though limited, highlight genomic differences between histologic subsets and outcome as well as the need for combination strategies that drive the recruitment and/or priming of anti-tumor T cells and address low immune permissive tumor states in patients with advanced solid tumors. Clinical trial registration: This clinical trial was registered on clinicaltrials.gov NCT03217747.