Inhibition of KRAS-dependent lung cancer cell growth by deltarasin: blockage of autophagy increases its cytotoxicity

Abstract

Deltarasin is a recently identified small molecule that can inhibit KRAS–PDEδ interactions by binding to a hydrophobic pocket on PDEδ, resulting in the impairment of cell growth, KRAS activity, and RAS/RAF signaling in human pancreatic ductal adenocarcinoma cell lines. Since KRAS mutations are the most common oncogene mutations in lung adenocarcinomas, implicated in over 30% of all lung cancer cases, we examined the ability of deltarasin to inhibit KRAS-dependent lung cancer cell growth. Here, for the first time, we document that deltarasin produces both apoptosis and autophagy in KRAS-dependent lung cancer cells in vitro and inhibits lung tumor growth in vivo. Deltarasin induces apoptosis by inhibiting the interaction of with PDEδ and its downstream signaling pathways, while it induces autophagy through the AMPK-mTOR signaling pathway. Importantly, the autophagy inhibitor, 3-methyl adenine (3-MA) markedly enhances deltarasin-induced apoptosis via elevation of reactive oxygen species (ROS). In contrast, inhibition of ROS by N-acetylcysteine (NAC) significantly attenuated deltarasin-induced cell death. Collectively, these observations suggest that the anti-cancer cell activity of deltarasin can be enhanced by simultaneously blocking “tumor protective” autophagy, but inhibited if combined with an anti-oxidant.

MEK nuclear localization promotes YAP stability via sequestering β-TrCP in KRAS mutant cancer cells

“…Deltarasin is a new small molecular inhibitor that suppresses oncogenic KRAS signalling by disrupting the binding of KRAS to its transporter PDEδ, preventing KRAS localizing to endomembranes [4]. Inhibition of mutant KRAS activity, cell growth, and tumour dissemination by deltarasin has been reported in pancreatic cancer, lung cancer and colon cancer [4, 26, 27]. By IF and WB assays, deltarasin had similar effects on MEK/β-TrCP nuclear localization and YAP levels (Fig.…”

Grifolin, neogrifolin and confluentin from the terricolous polypore Albatrellus flettii suppress KRAS expression in human colon cancer cells

“…KRAS is an elusive oncotarget and much effort continues to focus on targeting it by directly inhibiting its function, biogenesis and expression [14,35]. Furthermore, constitutively active KRAS has been linked to increased cell proliferation [36][37][38]. Therefore, we investigated…”

Identification of a new inhibitor of KRAS‐PDEδ interaction targeting KRAS mutant nonsmall cell lung cancer

“…32 However, subsequent detailed analysis of the characteristic dose–response curves of deltarasin reveals that this PDEδ ligand displays a ‘switch‐like’ inhibition of proliferation exhibiting cytotoxic effects at concentrations above 9 μM in all tested cell lines, including cancer and normal cells . Our research revealed another limitation of deltarasin, it induces protective autophagy in non‐small cell lung cancer . Additionally, a second inhibitor with similar biochemical potency to deltarasin, deltazinone 1, was rapidly metabolized in in vivo experiments, although it showed a higher binding affinity to PDEδ .…”

“…32 Our research revealed another limitation of deltarasin, it induces protective autophagy in non-small cell lung cancer. 33 Additionally, a second inhibitor with similar biochemical potency to deltarasin, deltazinone 1, was rapidly metabolized in in vivo experiments, although it showed a higher binding affinity to PDEδ. 34 Therefore, further challenges of drug discovery and chemical structure optimization will be required to fulfill an unmet medical need.…”