In pancreatic ductal adenocarcinoma (PDAC), KRAS mutations drive both cancer cell growth and formation of a dense stroma. Small molecule KRAS inhibitors (KRASi) represent a breakthrough for PDAC treatment hence clinical tools that can assess early response, detect resistance and/or predict prolonged survival are desirable for management of patients undergoing KRASi therapy. We hypothesized that diffusion-weighted MRI (DWI) can detect cell death while dynamic contrast enhanced MRI (DCE) and magnetization transfer ratio (MTR) imaging are sensitive to tumor microenvironment changes, and these metrics shed insights into tumor size (standard care assessment) change induced by KRASi treatment. We tested this hypothesis in multiple preclinical PDAC models receiving MRTX1133, an investigational new drug specific for KRAS G12D mutation. Quantitative imaging markers corroborated by immunohistochemistry (IHC) revealed significant and profound changes related to cell death accompanied by changes in tumor cellularity, capillary perfusion /permeability and stromal matrix as early as 48h and day-7 after initiation of KRASi treatment, and greatly prolonged median survival over controls in a genetic engineered mouse model of PDAC (KPC). The MRI markers also captured distinct responses to KRASi therapy from PDAC tumors carrying KRAS G12C versus KRAS G12D mutation. In tumors developed resistance to MRTX1133, the imaging markers exhibited a reversal from those of responding tumors. Our findings have established that multiparametric MRI provide biological insights including cell death, reduced cellularity and tumor microenvironment changes induced by KRASi treatment and set the stage for testing the utility of these clinically ready MRI methods in patients receiving KRASi therapy.
Translational relevance: Emerging small molecule KRAS inhibitors (KRASi) represent a new class of therapy for PDAC. Clinical tools that can provide biological insights beyond tumor size change are desirable for management of patients under KRASi therapy. DWI and DCE are frequently applied MRI methods for assessing cancer treatment responses in clinical trials. Using multiple PDAC models, we examined whether DWI, DCE and MTR can enhance the standard care assessment (tumor size) to MRTX1133, a KARSi with investigational new drug (IND) status. Our data demonstrate the abilities of DWI, DCE and MTR derived imaging markers to detect the early (48h) cell death, pronounced stromal changes and development of resistance to KRASi. This study has high translational relevance by testing clinically ready MRI methods, an IND and a genetic engineered mouse model that recapitulates saline features of human PDAC.