Abstract C143: Unveiling synergistic interplay between KRASG12C inhibitors and the polyamine synthesis inhibitor SAM486 against lung cancer cells: An in vitro study

Abstract

Abstract Introduction: Non-small cell lung cancer (NSCLC) represents the most lethal variant of lung cancer. The G12C mutation in the KRAS protein occurs in 20-30% of NSCLC patients and is correlated with an unfavorable prognosis. Adagrasib and sotorasib are emerging compounds that inhibit the KRASG12C protein, demonstrating effectiveness in NSCLC driven by KRASG12C. However, the early development of resistance to KRASG12C inhibitors emphasizes the necessity to investigate combined therapeutic approaches. Polyamines (putrescine, spermidine, and spermine) are essential molecules for cancer growth and survival and are elevated in various cancer types, including NSCLC. Adenosylmethionine decarboxylase-1 (AMD1) is a critical enzyme involved in spermidine and spermine synthesis. AMD1 depends on KRAS signaling via the IGF-AKT-mTOR signaling and can be selectively restrained by the compound SAM486. Aim: This study aimed to explore the effect of AMD1 inhibition in NSCLC cells using the compound SAM486, alone or in combination with the KRASG12C inhibitors adagrasib and sotorasib, and to investigate the relationship between KRASG12C inhibition and polyamine enzyme levels. Methods: We employed four NSCLC cell lines: H358 (KRASG12C), A549 (KRASG12S), CORL-L23 (KRASG12V), and H1299 (KRASwt). Immunoblotting analysis was utilized to measure AMD1 levels and KRAS-ERK pathway phosphorylation. Cell proliferation was assessed through BrdU incorporation and colony formation assays. Cell viability was determined by MTT reduction, and combination studies were evaluated using Combenefit and SynergyFinder software, employing the Loewe additivity model. Results: The AMD1 inhibitor SAM486 exhibited a reduction in cell proliferation in NSCLC cells, irrespective of the presence of KRAS mutations. Furthermore, the KRASG12C inhibitors sotorasib and adagrasib decreased AMD1 levels and cell viability in H358 cells harboring the KRASG12C mutation. Notably, a high degree of synergy was observed when combining sotorasib and adagrasib with SAM486 in KRASG12C-mutated cells, as evaluated by Combenefit and SynergyFinder software, employing the Loewe additivity model. Conclusion: These findings suggest that the simultaneous inhibition of KRASG12C and AMD1 could provide a novel and synergistic therapeutic strategy against tumors with KRASG12C mutations. Citation Format: Rodrigo A Lopez-Muñoz, Antonia Martin-Martin, Carina Chipon, Neudo Buelvas, Sergio Guzmán-Kunstmann, Matías Mansilla-Velásquez. Unveiling synergistic interplay between KRASG12C inhibitors and the polyamine synthesis inhibitor SAM486 against lung cancer cells: An in vitro study [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C143.