Abstract 11P
Background
KRAS is the most frequently mutated gene in appendiceal adenocarcinoma (AA) (45.6%) with just over half (50.4%) being G12D. Unique to AA, KRAS mutant tumors are strongly enriched for co-mutation with GNAS(odds ratio 12.2; p = 7.8x10-40, 45% of KRASmut have co-mutant GNAS). The KRAS-G12D inhibitor MRTX1133 has shown robust anti-cancer activity in pre-clinical models of pancreatic, lung and colon cancer (CRC). Here we explore MRTX1133 in orthotopic PDX models of KRASG12D AA.
Methods
Four AA and CRC organoid models were developed and treated with MRTX1133. Orthotopic AA PDX models with KRASG12D were established by intraperitoneal implantation (TM00351 from Jackson Laboratory) and were intraperitoneally treated with MRTX1133 (15 mg/kg) (N=3) or vehicle (10% Captisol/50 mM citrate pH 5.0) (N=3), BID for 28 days. Tumor samples were analyzed using H&E, IHC, and RNAseq.
Results
KRASG12D but not KRASG12V organoids were sensitive to treatment with single-agent MRTX1133 (IC50 4.1 nM vs 1.8 uM, F-test, p < 0.0001). In PDX models IP MRTX1133 significantly reduced tumor volume relative to control as measured by MRI (1.15 vs 2.39, p =0.04). MRTX1133-treated tumors displayed low cellularity, with few cells positive for Ki-67 and a marked reduction in pERK, consistent with reduced cell proliferation and inactivation of RAS-MAPK pathway. Gene Sets Enrichment Analysis (GSEA) confirmed significant downregulation of E2F targets (NES = -1.9, FDR = 0.06) and RAS/ERK upregulated (NES = -2.3, FDR = 0.06) gene sets in MRTX1133-treated tumors. Interestingly, overexpression of GNASR201C (but not GNASWT ) in C479T organoids (AA) conferred resistance to KRAS-G12D inhibition (IC50 2.1 vs 5.9 nM, p < 0.0001). LS174T (CRC) organoid models were 100 fold less sensitive to MRTX1133 relative to AA models, but similarly expressing GNASR201C conferred resistance (IC50 360 nM vs >5 uM, p < 0.0001).
Conclusions
To our knowledge, this is the first report of activity of a KRAS inhibitor in pre-clinical models of AA. AA Models with KRASG12D were highly sensitive to MRTX1133 monotherapy providing a clear rationale for clinical testing. However, the presence of GNASR201C appears to cause resistance, suggesting a combination strategy may be required in KRASG12D/GNASmut tumors.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
This work was supported by the Colonel Daniel Connelly Memorial Fund, the National Cancer Institute (grant No. K22 CA234406 to Dr Shen, Cancer Center Support grant No. P30 CA016672), the Cancer Prevention and Research Institute of Texas (CPRIT) (grant No. RR180035 to Dr Shen, who is a CPRIT Scholar in Cancer Research), and a Conquer Cancer Career Development Award.
Disclosure
J.P.Y. Shen: Financial Interests, Personal, Other, general consultation and expert testimony: ShenJPMD Inc; Financial Interests, Personal, Other, advisory board: Engine Biosciences, NaDeNo Nanosciences; Financial Interests, Institutional, Coordinating PI, research project: Celsius Therapeutics; Financial Interests, Institutional, Other, research funding for pilot project: BostonGene. All other authors have declared no conflicts of interest.
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