Abstract 1072: Combination of 5-Fluorouracil or ONC212 plus KRAS G12D inhibitor MRTX1133 against colorectal and pancreatic cancer cells results in immune-stimulatory cytokine patterns and unexpected synergies independent of G12D mutation

Abstract

BACKGROUND: Advanced metastatic colorectal cancer (mCRC) has a 14% 5-year survival rate with little progress made for microsatellite stable tumors. KRAS mutations occur in about 40-50% of mCRC and are associated with more aggressive drug resistance and lack of response to anti-EGFR therapies. Recent advances have led to small molecules targeting KRAS G12C that have been undergoing clinical testing in lung, mCRC, and other tumor types. ONC212 is a fluorinated imipridone with strong anti-cancer activity in nM range and preclinical efficacy against pancreatic and other malignancies. Through extensive structure-based drug design, MRTX1133 was identified as a noncovalent, potent, and selective inhibitor of KRASG12D. MRTX1133 suppresses KRASG12D signaling in cells and in vivo, MRTX1133 binds to the switch II pocket and inhibits the protein-protein interactions necessary for activation of the KRAS pathway. MATERIALS & METHODS: We investigated cell viability and drug synergies of 5-FU or ONC212 plus KRAS G12D inhibitor MRTX1133 in 6 human CRC and 4 human pancreatic cancer cell lines at 72 hours. Experiments evaluated drug effects on pERK using western blot at 6 and 24 hours. We evaluated changes at 48 hours in cytokine profiles in treated cells using a custom panel of 62 cytokines, chemokines, and growth factors associated with tumor growth, immune stimulation or immune suppression. RESULTS: Colorectal and pancreatic cancer cell lines had IC50 sensitivities ranging from 7 to 12 microM for 5-FU 0.2-0.8 microM for ONC212, >100 nM to >5,000 nM for MRTX1133 (G12D N=4: LS513 >100, HPAF-II >1,000, SNUC2B >5,000, PANC-1 >5,000). For non-G12D, the range of IC50 for MRTX1133 was >1,000 to >5,000 nM for CRC lines with G12V, G13D, or WT KRAS (N=7). Synergies between MRTX1133 and either 5-FU or ONC212 were observed across cell lines regardless of the presence of KRAS G12D mutation with combination indices of <0.5 indicating strong synergy. The observed synergy was greater with the combination of MRTX1133 and ONC212 compared to the synergy with 5-FU. Among the cytokine alterations, IL8/CXCL8, MICA, Angiopoietin 2, VEGF and TNF-alpha were reduced while IL-18/IL-1F4 increased with all treatments. CONCLUSIONS: Our ongoing studies reveal the potential activity of MRTX1133 against mCRC and pancreatic cancer cells regardless of KRAS G12D mutation and synergies were observed with 5-FU and ONC212 regardless of KRAS G12D mutation. Immune stimulatory cytokine profiles were observed with 5-FU, MRTX1133 and combination. The results suggest that KRAS G12D, KRAS G13D and WT KRAS should not be excluded from clinical trials especially with combination therapies involving MRTX1133 and standard-of-care 5-FU. Citation Format: Vida Tajiknia, Wafik El-Deiry, Maximilian Pinho Schwermann, Lanlan Zhou, Kelsey Huntington. Combination of 5-Fluorouracil or ONC212 plus KRAS G12D inhibitor MRTX1133 against colorectal and pancreatic cancer cells results in immune-stimulatory cytokine patterns and unexpected synergies independent of G12D mutation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1072.

Genetic Signature of Human Pancreatic Cancer and Personalized Targeting

“…At the time of writing this review, there is solid preclinical evidence of MRTX1133 as an effective and potent inhibitor of KRAS G12D with benefits in PDAC, but there is no information about patient treatments [154][155][156][157]. There is one ongoing clinical trial, which is of MRTX1133 in patients with advanced solid tumors harboring a KRAS G12D mutation (NCT05737706).…”