Overcoming KRAS-Inhibitor Resistance: Absin Organoid Culture Kit Powers SAT1–Polyamine–Ferroptosis Precision-Oncology Study

KRAS mutations drive pancreatic, colorectal, and lung adenocarcinomas. Although KRAS^G12C inhibitors such as sotorasib are approved, co-occurring KEAP1 mutations confer profound resistance. The authors hypothesized that:

• 1. Tumor cells depend on polyamine metabolism for proliferation; targeting this pathway could sensitize tumors to KRAS inhibition;
• 2. KEAP1 status dictates expression of polyamine-metabolic enzymes and thus therapeutic response;
• 3. Polyamine metabolism intersects with ferroptosis, offering a synergistic anti-cancer modality.

A step-wise pipeline—metabolite library screening → cell/organoid validation → mechanistic dissection → in-vivo confirmation—ultimately defined a KRAS–KEAP1–SAT1–ferroptosis regulatory axis and a genotype-guided treatment paradigm.

1. Polyamine supplementation sensitizes in a KEAP1-dependent manner

• In KRAS^MU/KEAP1^WT cells, patient-derived organoids (PDOs), and xenografts, exogenous spermidine or spermine markedly enhanced KRAS-inhibitor efficacy (Fig. 1H–K);
• KRAS^MU/KEAP1^MU models required lentivirus/AAV-mediated SAT1 over-expression plus polyamine supplementation to achieve sensitization (Fig. 6C–D).

2. SAT1 is the central metabolic node

SAT1 (spermidine/spermine N¹-acetyltransferase) is rate-limiting for polyamine catabolism and is regulated by KEAP1 status:

• In KEAP1^WT cells, KRAS inhibition activates the JNK/c-Jun axis, up-regulating SAT1, promoting polyamine catabolism, ROS accumulation, and ferroptosis (Fig. 5A);
• In KEAP1^MU cells, constitutive NRF2 activation accelerates JNK degradation, repressing SAT1; exogenous SAT1 restoration is required to re-sensitize tumors (Fig. 2H).

3. Overcoming acquired resistance

Long-term sotorasib-resistant cells remained susceptible to the polyamine–SAT1 regimen, which restored lipid-ROS accumulation and elevated MDA levels, confirming ferroptotic cell death (Fig. 4H) and offering a salvage strategy for resistant disease.

Absin PDO reagents provided robust, reproducible organoid models for all functional assays:

Patient-derived organoids faithfully recapitulate in-vivo tumor biology and have become a cornerstone of precision-oncology research. Absin’s PDO culture kits, recognized for robustness and batch-to-batch consistency, accelerated the clinical translation of the polyamine-sensitization strategy.

This study establishes KEAP1 genotype as a decisive biomarker for polyamine-targeted interventions and proposes a stratified regimen: KRAS inhibitor + polyamine supplementation (KEAP1-WT) versus SAT1 over-expression + polyamine supplementation + KRAS inhibitor (KEAP1-mutant), setting a new paradigm for precision oncology in KRAS-driven cancers.