2551 - Carbon Ion Radiotherapy Synergizes with KRASG12D Inhibition to Overcome Acquired Resistance In Pancreatic Cancer
Presenter(s)
H. J. Meyer1, M. Moustafa2, S. Eskandarian3, T. Wang4, L. Wang4, M. Akbarpour2, S. Magdeldin5, N. Abdallah5, A. Osama5, U. Titt1, S. Brons6, A. C. Koong7, A. Abdollahi8, D. Jiang4, and R. Mohan1; 1Department of Radiation Physics, The University of Texas MD Anderson Cancer Center, Houston, TX, 2Division of Molecular and Translational Radiation Oncology, Department of Radiation Oncology, Heidelberg Faculty of Medicine (MFHD), Heidelberg University Hospital (UKHD) and Heidelberg Ion-Beam Therapy Center (HIT), Heidelberg, Germany, 3DKFZ/HIT/NCT/UKHD, Heidelberg, Germany, 4Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 5Children Cancer Hospital Egypt 57357, Cairo, Egypt, 6Department of Radiation Oncology, University Hospital Heidelberg, Heidelberg, Germany, 7Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 8Clinical Cooperation Unit Translational Radiation Oncology, National Center for Tumor Diseases (NCT), Heidelberg University Hospital (UKHD) and German Cancer Research Center (DKFZ), Heidelberg, Germany
Purpose/Objective(s): Despite advances in immunotherapies and targeted therapies, pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, with an overall 5-year survival of approximately 13%. Enhanced relative biological effectiveness (RBE) Carbon Ion Radiotherapy (CIRT) may provide a promising tool to eradicate therapy-resistant tumors such as PDAC. Novel KRASG12D inhibitors (MRTX1133) have demonstrated tumor control via a CD8+ T-cell-dependent mechanism in PDAC; however, post-therapy resistance frequently develops. We hypothesized that CIRT-induced tumor immune microenvironment (TIME) remodeling would synergize with KRASG12D inhibition to enhance tumor control and resensitize KRAS-inhibitor–resistant PDAC.
Materials/Methods: In vivo studies employed C57BL/6 syngeneic PDAC derived from KPC mice (LSL-Kras^G12D/+;LSL-Trp53^R172H/+;Pdx-1-Cre). An acquired-resistant line (MRTXR-603) was generated after orthotopic implantation of KPC cells, continuous MRTX1133 inhibitor treatment, and derivation of the recurrent cell line. KPC or MRTXR-603 cells were implanted subcutaneously into the right hind limb of C57BL/6 mice. Tumors received 5 fx of 3 Gy physical dose of 225 kVp photon radiation or carbon ion radiation (95 keV/µm LETd), ±MRTX1133 (7 days, i.p., b.i.d.). Thymus, spleen, lymph node, and tumor tissues were collected 48 hours post-radiation and at tumor growth endpoint for IHC and spatial transcriptomic analysis of the immune compartment. Tumor growth delay and elimination were assessed across treatment groups.
Results: In KPC tumors, MRTX1133 produced greater tumor growth delay than radiotherapy alone, while combined CIRT and MRTX1133 treatment achieved the greatest tumor control. MRTX1133 alone eliminated tumors in 4/5 mice, and MRTX1133+CIRT eliminated tumors in 5/6 mice. In resistant MRTXR-603 tumors, MRTX1133 alone had minimal efficacy. Photon radiotherapy combined with MRTX1133 modestly delayed tumor growth and did not result in any tumor eliminations (0/6), whereas CIRT combined with MRTX1133 resulted in tumor elimination in 4/6 mice and significant tumor growth delay compared to control in 2/6 mice (52.5 day median survival vs. 15 day median survival). As previous studies have shown MRTX1133 to eliminate tumors in a CD8+ T-cell-mediated manner, immune profiling is ongoing to define treatment-associated changes in the TIME and will be presented at the conference.
Conclusion: As KRAS inhibitors for pancreatic cancer move towards clinical use, it is vital to understand interactions and synergies with current standard of care techniques and to understand mechanisms of resistance. These findings demonstrate a strong therapeutic synergy between RT and KRASG12D inhibition, with greater synergy when using high-LET CIRT, motivating mechanistic studies of immune remodeling in multi-modal therapy and supporting this combination as a promising strategy to overcome resistance and improve outcomes for patients with pancreatic cancer.