Decoding KRAS signaling intensity: A key driver of tumor aggressiveness and response to RAS inhibition in pancreatic cancer

Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy, with KRAS mutations present in near 90% of cases, most frequently in codons 12 and 61. Increased KRAS copy number, resulting in elevated KRAS signaling intensity, correlates with poor prognosis and limited chemotherapy response. However, the role of KRAS signaling intensity in PDAC initiation, progression, and response to treatment remains unclear due to the lack of suitable in vivo models. Methods: We developed a unique set of pancreatic cancer mouse models ranging from low to high levels of KRAS signaling by crossing the Pdx1-CreER (+) / Trp53 (fl/fl) mice with Cre-inducible Kras -LSL G12D or Kras -LSL Q61R alleles that either express these oncogenic alleles with native codons (low expression) or optimized codons (high expression). Tumor onset, progression, metastasis, and survival were systematically assessed. Additionally, 24 murine PDAC cell lines were established from these models, and eight human PDAC cell lines were classified into low- and high-intensity KRAS signaling groups to evaluate therapeutic response to the pan-RAS inhibitor RMC-6236. Results: KRAS signaling intensity profoundly influences the timing of PDAC onset, disease progression, and metastatic potential. Mice with high, intermediate, and low KRAS signaling developed PDAC at approximately 4-5, 12-16, and 16-24 weeks of age, respectively. Survival analysis over a 52-week period revealed striking differences in overall survival, with median survival times of 8 weeks (high), 23 weeks (intermediate), and 41 weeks (low). Notably, the high-intensity group exhibited significantly higher rates of distant metastases to the lung and liver compared with the intermediate- and low-intensity groups. In vitro treatment suggested that cells with lower KRAS signaling intensity tended to be more sensitive to RMC-6236, highlighting its potential as a biomarker for patient stratification and therapeutic decision-making. Conclusions: KRAS signaling intensity is a key determinant of PDAC initiation, progression, metastasis, and overall clinical outcomes. Moreover, it may serve as a predictive biomarker for response to RAS-targeted therapies. Collectively, these findings suggest that quantifying KRAS signaling intensity could enable precision medicine approaches and guide therapeutic decision-making in PDAC.Generative AI tools were used to assist with text editing and improvement of this abstract.