Abstract B072: Resistance to the RAS inhibitor daraxonrasib due to the LZTR1 mutation in a KRAS G12D mutated pancreatic ductal adenocarcinoma patient-derive
Alexa F. Viniotis, Jaeger Moore, Raffaella Soldi, Erkut H. Borazanci, Sunil SharmaAbstract
Introduction:
Targeted therapy with RAS (Rat sarcoma) inhibitors are increasingly used in the treatment of pancreatic ductal adenocarcinoma (PDAC) given the prevalence of KRAS (Kirsten rat sarcoma virus) mutations in over 90% and poor prognosis with 13.7% five-year survival in this population despite standard treatment.1,2 Leucine zipper-like translational regulator 1 (LZTR1) aids in KRAS ubiquitin-mediated degradation so patients with loss of function (LOF) mutations in LZTR1 lack response to RAS inhibitors.3 We report a case where a pancreatic cancer organoid showed resistance to a pan-RAS inhibitor due to the LZTR1 mutation.
Case Description:
The patient is a 73-year-old female who was diagnosed with PDAC in February 2025. Molecular testing showed CDKN2A, KRAS G12D, KMT2D, TP53, CTRC, and LZTR1 mutations. She was treated with FOLFOX (5-fluorouracil, oxaliplatin, and leucovorin) for 3 cycles starting in mid-March 2025 and then transitioned to NALIRIFOX with the addition of liposomal irinotecan at the end of April through October 2025. Imaging revealed disease progression with liver metastases confirmed on biopsy from 5/14/2025.
Methods:
Patient’s biopsy was processed by enzymatic and mechanic dissociation to obtain a single cell suspension comprised of tumor and stroma cells. Patient-derived cells were treated with the single agent multi-selective RAS(ON) inhibitor daraxonrasib (RMC-6236) and combination of RMC-6236 with the mTOR inhibitor everolimus in 2D and 3D viability assays. Patient-derived organoids (PDOs) were generated by combining tumor and stroma in a 1:1 ratio and allowing formation for 72 hours. Organoids were exposed to 8 point 2-fold serial dilution for 72 hours. Synergistic data was analyzed using Bliss Synergy with Combenefit, and 2D dose response data was analyzed using GraphPad Prism; student t-test was used for statistical significance. Patient cells were treated for western blot analysis, investigating RAS-MAPK pathway inhibition and apoptotic markers.
Results:
Testing of RMC-6236 in PDOs showed minimal single agent activity. In contrast, the combination of RMC-6236 with the mTOR inhibitor everolimus produced a clear synergistic response, indicating that mTOR blockade may overcome adaptive resistance mechanisms limiting RMC-6236 monotherapy efficacy.
Conclusions:
Despite having a KRAS G12D mutation, this patient’s organoid likely had resistance to the pan-RAS inhibitor due to their heterozygous LZTR1 mutation. Genetic mutations may impact a drug’s mechanism of action and alter treatment response. Combination with drugs such as mTOR inhibitors may help overcome this resistance. PDOs are an effective model for preliminary drug testing and translation into the clinical setting.
Citation Format:
Alexa F. Viniotis, D.O., Jaeger Moore, B.S., Raffaella Soldi, Ph.D., Erkut H. Borazanci, M.D., M.S., Sunil Sharma, M.D. Resistance to the RAS inhibitor daraxonrasib due to the LZTR1 mutation in a KRAS G12D mutated pancreatic ductal adenocarcinoma patient-derived organoid model [abstract]. In: Proceedings of the AACR Conference on Pancreatic Cancer: New Frontiers in Biology and Therapeutic Development; 2026 Sep 25-28; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(18_Suppl_2):Abstract nr B072.