Abstract 2665: Irreversible menin inhibitor, BMF-219, inhibits the growth of KRAS-mutated solid tumors
Authors: Law Brian , Lu Daniel , Somanath Priyanka , Palmer James T. , Kinoshita Taisei , Butler Thomas 
Published: June 2022

Abstract
Introduction: KRAS (Kirsten rat sarcoma virus) is the most frequently mutated isoform amongst RAS oncogenes in human solid tumors being present in a high percentage of colorectal cancers (CRC), non-small cell lung cancers (NSCLC), and pancreatic cancers. With only one approved KRAS G12C inhibitor for NSCLC, KRAS-driven tumors continue to represent a significant unmet medical need where novel effective therapies are highly desired. Menin is a required co-factor of oncogenic transcriptional proteins with functional interactions that are critical for various malignancies including acute leukemia. We previously reported that BMF-219, a novel irreversible menin inhibitor, exhibits strong potency on acute leukemia (MOLM-13) and KRAS-mutant (MiaPaCa-2) cells. Results from MiaPaCa-2 cells prompted our exploration of the effects of BMF-219 in an expanded panel of KRAS-mutant solid tumors through in vitro and ex vivo preclinical models.
Methods: BMF-219, clinical reversible menin inhibitors, or clinically approved KRAS G12C inhibitor, sotorasib, were cultured with CRC, NSCLC, pancreatic cancer cell lines for 4-days. Human ex vivo preclinical models harboring KRAS mutations were cultured with BMF-219 and reversible menin for 6-days. Cell viability was measured using CellTiter Glo and IC50 values were calculated. MiaPaCa-2 cells incubated with BMF-219 were analyzed by RNA-seq on the Illumina NextSeq 550 platform.
Results: MiaPaCa-2, a KRAS G12C-mutant cell line, showed marked reduction of KRAS expression levels following 24 hours of BMF-219 treatment at 0.5 µM. An expanded panel of 14 CRC, NSCLC and pancreatic KRAS-mutant cell lines harboring G12C, G12D, G12V, and Q61L revealed single-agent BMF-219 activity after a 4-day treatment. Majority of the cell lines tested exhibited &gt;90% inhibition of growth, independent of KRAS mutation type. Sotorasib reached a maximum of 90-93% growth inhibition in three of eight cell lines. By contrast, BMF-219 inhibited cell viability ≥ 90% in six of eight KRAS G12C lung cancer lines. Human CRC, NSCLC and pancreatic ex vivo preclinical models with G12C, G12D, and G12V KRAS mutations were all sensitive to BMF-219 after a 6-day treatment. Complete abrogation of growth was observed in all samples with IC50 values ranging between 0.2 μM - 0.6 μM.
Conclusion: KRAS-mutant CRC, NSCLC, pancreatic cancer cell lines and ex vivo preclinical models are highly sensitive to irreversible menin inhibitor, BMF-219, where clinical reversible menin inhibitors displayed limited activity. High potency of BMF-219 was observed amongst various KRAS-mutant cell lines suggesting that BMF-219 broadly inhibits these tumors. As an irreversible menin inhibitor, BMF-219, manifests advantages over the KRAS-targeted inhibitor sotorasib in multiple cell lines tested, and displays unique potency compared with clinical reversible menin inhibitors in ex vivo preclinical models of CRC, NSCLC, and pancreatic cancer.
Citation Format: Brian Law, Daniel Lu, Priyanka Somanath, James T. Palmer, Taisei Kinoshita, Thomas Butler. Irreversible menin inhibitor, BMF-219, inhibits the growth of KRAS-mutated solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2665.