Radiation Particle Type and Tumor Immune Microenvironment Modulate KRAS Inhibitor-Radiotherapy Synergy and Overcome KRAS Inhibitor Resistance In Pancreatic Cancer
Abstract
Purpose
Enhanced relative biological effectiveness (RBE) Carbon Ion Radiotherapy (CIRT) may provide a promising tool to eradicate therapy-resistant tumors such as pancreatic ductal adenocarcinoma (PDAC). Novel KRASG12D inhibitors have demonstrated CD8+ T-cell dependent tumor control in PDAC; however, post-therapy resistance frequently develops. We hypothesized that CIRT-induced activation of the adaptive immune response would synergize with KRASG12D inhibition to enhance tumor control and resensitize KRAS-inhibitor–resistant PDAC.
Methods
In vivo studies employed a C57BL/6 syngeneic pancreatic ductal adenocarcinoma (PDAC) genetically engineered mouse model (GEMM) derived from LSL-Kras^G12D/+;LSL-Trp53^R172H/+;Pdx-1-Cre; KPC mice. To model acquired resistance, KRASG12D inhibitor–resistant tumors were generated through orthotopic implantation of KPC cells, continuous KRASG12D inhibitor treatment, and derivation of the recurrent “MRTXR-603” cell line. KPC or MRTXR-603 cells were implanted subcutaneously into the right hind limb of C57BL/6 mice. Tumors received 3 Gy × 5 fractions of either 225 kVp photon irradiation or carbon ion irradiation (95 keV/µm LETd), with or without KRASG12D inhibition. Thymus, spleen, abdominal lymph node, and tumor tissue were collected 48 hours post-radiation and at tumor growth endpoint for immunohistochemical and spatial transcriptomic analysis of the immune compartment. Tumor growth delay and elimination were assessed across treatment groups.
Results
In KPC tumors, KRASG12D inhibition produced greater tumor growth delay than radiotherapy alone, while combined radiotherapy and KRAS inhibition achieved the greatest tumor control. In resistant MRTXR-603 tumors, KRAS inhibition alone had minimal efficacy. Photon radiotherapy combined with KRAS inhibition modestly delayed tumor growth, whereas carbon ion radiotherapy combined with KRAS inhibition resulted in tumor elimination in most cases. Ongoing analyses to elucidate the role of radiation modulated immune responses will be presented at the conference.
Conclusion
These findings demonstrate a strong therapeutic synergy between CIRT and KRASG12D inhibition, supporting this combination as a promising strategy to overcome resistance and improve outcomes in pancreatic cancer.