Multimetric MRI Captures Early Response and Acquired Resistance of Pancreatic Cancer to KRAS Inhibitor Therapy

Abstract Purpose: In pancreatic ductal adenocarcinoma (PDAC), Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations drive both cancer cell growth and formation of a dense stroma. Small-molecule KRAS inhibitors (KRASi) represent a promising new class of therapy for PDAC; hence, clinical tools that can assess early response, detect resistance, and/or predict prolonged survival are desirable to understand clinical biology of KRASi. We hypothesized that diffusion-weighted MRI can detect cell death, whereas dynamic contrast-enhanced MRI and magnetization transfer ratio imaging are sensitive to tumor microenvironment changes, and these metrics shed insights into tumor size change induced by KRASi treatment. Experimental Design: Multiple preclinical PDAC models, including a genetically engineered mouse model (KPC), received MRTX1133, a KRASi specific for KRASG12D mutation. Quantitative imaging markers were corroborated with IHC analyses. Results: A significant increase in tumor apparent diffusion coefficient (a diffusion-weighted MRI metric) was detected as early as 48 hours and persisted to day 7 after the initiation of KRASi treatment and was strongly correlated with cell death and reduced cellularity, resulting in greatly prolonged median survival in treated mice. Capillary perfusion/permeability (a dynamic contrast-enhanced MRI metric) exhibited an inverse relationship with microvascular density. Distinct responses of KRASG12C versus KRASG12D tumors to MRTX1133 were captured by the MRI metrics corroborated with IHC. When tumors developed resistance to MRTX1133, the imaging marker values exhibited a reversal from those of responding tumors. Conclusions: Multiparametric MRI provides early biological insights of cancer and stromal responses to KRASi treatment and sets the stage for testing the utility of these clinically ready MRI methods in patients receiving KRASi therapy.