KRAS G12D

Herein we outline the biology and epidemiology of KRAS alterations at the lineage and allele levels, reviewing the clinical evidence for KRASG12C inhibition from the discovery of the recessive switch pocket to sotorasib, adagrasib and other novel molecules, and extending to the non-KRASG12C era, including RAS (ON)- and KRASG12D-selective strategies and early efficacy signals. We propose a 'three-clock, two-window' framework, which includes half-life exposure, occupation retention and extracellular signal-regulated kinase (ERK) rebound calibration of dosing rhythm; a vascular normalization window and an immune/myeloid plasticity window to achieve longitudinal Src homology 2-containing protein tyrosine phosphatase 2/son of sevenless homologue 1 and transverse epidermal growth factor receptor, phosphoinositide 3-kinase-protein kinase-mammalian target of rapamycin synergy. At the same time, we construct and propose a closed loop of exposure, occupation, pathway inhibition, circulating tumour DNA (ctDNA) and imaging by utilizing ctDNA dynamics, phosphorylated ERK rebound and perfusion imaging, as well as myeloid lineage quantification, to improve durable inhibition and overall survival through time-aligned combined effects.

In localized PDAC, KRAS-mutant ctDNA detected by NGS or ddPCR was associated with worse survival. ddPCR identified additional patients missed by NGS. Integrating ddPCR with NGS ctDNA measures may improve perioperative risk stratification, though validation is needed before clinical implementation.

Despite apparently favorable pathological staging and adjuvant FOLFIRINOX chemotherapy, the patient developed early biochemical progression with rapidly rising carbohydrate antigen 19-9 (CA 19-9) levels, followed by widespread metastatic dissemination involving the liver, lung, spine, skeletal muscle, and multiple visceral sites...This case highlights the limitations of anatomical staging in PDAC and emphasizes the prognostic importance of tumor biology, including KRAS mutation status, lymphovascular invasion, and perineural invasion. It also demonstrates the potential limitations of CA 19-9 as a solitary marker of treatment response in biologically aggressive disease.

Using a paclitaxel (PTX)-resistant Lewis lung carcinoma cell line, we demonstrated that ERK-dependent Pgp1 functions as a shared upstream regulator of both chemoresistance and metastatic competence...Importantly, meta-analysis of clinical datasets further linked co-elevated FN and Pgp1 expression with poor prognosis and relapse in early-stage cancer patients, underscoring the translational relevance of targeting this shared pathway. These findings identify Mul A as a promising non-cytotoxic therapeutic candidate and elucidate the shared upstream molecular mechanism linking distinct downstream chemoresistance and metastasis.

TCRs that recognize the KRAS hotspot shared sequence motifs were found in several lung cancer patients. Our study highlights the successful generation of multi-valent KRAS-specific TCRs and supports the feasibility of targeting shared KRAS neoantigens through TCR engineering in lung cancer.

Subsequently, molecular dynamics (MD) simulation and MM-GBSA calculations rationalized its postulated binding towards KRAS G12D. This study provides an example of how to conduct an in-depth benchmarking approach for KRAS G12D and offering an evaluated SBVS protocol for it.

Initial binding and cell proliferation experiments show that some of the predicted hits exhibit high affinity (single digit nM) binding to KRAS and sub-to-low micromolar inhibitory activity in pancreatic cancer cell lines harboring G12D, G12V, or G12C KRAS mutations. Predicted to bind to the p2 (also called switch II) pocket of KRAS, these ligands harbor unique scaffolds compared to existing drugs or leads and may serve as useful starting points for the development of allele-specific or pan-KRAS inhibitors.

P1, N=20, Recruiting, Memorial Sloan Kettering Cancer Center

P3, N=300, Not yet recruiting, Genfleet Therapeutics (Shanghai) Inc.

This work suggests that targeting TMEM184A or its associated autophagic pathway could restore antigen presentation in MHC-I-deficient tumors, offering a potential combinatorial strategy to overcome adaptive immune resistance in multiple malignancies. Abbreviations: AKP organoids:apcandtrp53knockout, KRASG12Dmutation organoids; CRC: colorectal cancer; CQ: chloroquine; GABARAPL2/Atg8: GABA type A receptor associated protein like 2; IF: immunofluorescence; IFNG: interferon gamma; IHC: immunohistochemistry; MHC-I: major histocompatibility complex I; qRT-PCR: quantitative reverse transcription PCR; MSI-H: microsatellite instability-high; MSS: microsatellite-stable; TMEM184A: transmembrane proteins 184a.

FLT3L-cDC1 ISV represents a rational cytokine-enhanced cellular immunotherapy designed to overcome immunosuppression and restore DC function within the TME, thereby promoting tumor-specific adaptive immune responses and enhancing responsiveness to ICB.

Collectively, these approaches offer an avenue for reducing radioresistance in PDAC while improving treatment response and minimizing normal tissue toxicity. Future research directions should include the incorporation of multi-omics data into predictive models for appropriate treatment selection, additional large-scale, biomarker-driven clinical trials, and continued integration of biomarker-targeting drug therapy, radiotherapy, and immunotherapy into treatment regimens.