Drosophila Lung Cancer Models Identify Trametinib plus Statin as Candidate Therapeutic

Abstract

Summary We have developed a Drosophila lung cancer model by targeting Ras1G12V—alone or in combination with PTEN knockdown—to the Drosophila tracheal system. This led to overproliferation of tracheal tissue, formation of tumor-like growths, and animal lethality. Screening a library of FDA approved drugs identified several that improved overall animal survival. We explored two hits: the MEK inhibitor trametinib and the HMG-CoA reductase inhibitor fluvastatin. Oral administration of these drugs inhibited Ras and PI3K pathway activity, respectively; in addition, fluvastatin inhibited protein prenylation downstream of HMG-CoA reductase to promote survival. Combining drugs led to synergistic suppression of tumor formation and rescue lethality; similar synergy was observed in human A549 lung adenocarcinoma cells. Notably, fluvastatin acted both within transformed cells and also to reduce whole body trametinib toxicity in flies. Our work supports and provides further context for exploring the potential of combining statins with MAPK inhibitors such as trametinib to improve overall therapeutic index.

Cancer Drug Development Using Drosophila as an in vivo Tool: From Bedside to Bench and Back

“…The oncogenic phenotypes and lethality were further suppressed by the combination of the two agents. Similar observations were made in human lung cancer cell lines [94].…”

“…In another recent study, a Ras-phosphatase and tensin homolog deleted on chromosome 10 (PTEN) lung cancer model was developed in the Drosophila tracheal system [94]. The model was associated with overproliferation of tracheal tissue, formation of tumor-like growths, and animal lethality.…”

“…Inhibited the differentiation of stem cells into enterocytes [47] Acivicin Inhibited tumor formation in Drosophila by inhibiting CTP synthase [22] Gefitinib and erlotinib Suppressed eye and wing phenotypes induced by EGFR in Drosophila; inhibited dp-ERK1/2 in the eye and wing imaginal discs of wild-type larvae [56] Artemisinin, curcumin Exhibited anticancer activities against brain cancer through generation of reactive oxygen species [60] TAE684, crizotinib Ameliorated the rough-eye phenotype caused by overexpression of hALK F1174L and hALK R1275Q in Drosophila; the effect of crizotinib was less than that of TAE684 [70,71] Imipramine Inhibited fascin pathway in Drosophila; known mediator of tumor invasion and metastasis [76] Triptolide Induced apoptosis in third-instar larval wing discs of Drosophila by inhibiting the ATPase activity of the XPB subunit of TFIIH [84] F14512 Exhibited antiproliferative properties in Drosophila cells; stabilized ternary Topo II-DNA-cleavable complexes at unique sites located in moderately repeated sequences [87] AY9944 Inhibited Hh-induced internalization of the transmembrane protein Ptc as well as the expression of the Hh target gene en; depleted cholesterol from the plasma membrane and its intracellular accumulation in Drosophila tissues [89] Bouvardin Enhanced the effects of radiation in Drosophila larvae through inhibition of the elongation step of protein synthesis [92] Trametinib and fluvastatin Improved tracheal development and reduced over-proliferation and whole-animal toxicity in a Ras-PTEN Drosophila lung cancer model [94]. several aspects of tumor development [23], small molecules that disrupt the function of STAT, such as sunitinib and dasatinib, are now being developed for cancer therapy [24].…”

Cytoneme-mediated signaling essential for tumorigenesis

“…The high degree of evolutionary conservation with human proteins make Drosophila a clinically relevant platform for understanding mechanisms human disease, and Drosophila tumor models have successfully identified new therapeutic candidates for colorectal, lung and thyroid and stem-cells derived cancers (Bangi et al, 2016;Levine and Cagan, 2016;Markstein et al, 2014).…”

The phylogenetic functional conservation ofDrosophilaSeven-In-Absentia (SINA) E3 ligase and its two human paralogs, SIAH1 and SIAH2, inDrosophilaeye development

“…SIAH is a major tumor vulnerability and the most downstream gatekeeper of the oncogenic RAS/EGFR/HER2 signal transduction cascade [28][29][30][31][32]. Hence, the mechanistic insights of SINA/SIAH function gained from Drosophila genetic and mutagenesis studies will be easily translational, clinically relevant, and directly applicable to human cancer biology [66][67][68][69][70][71][72][73][74]. As we design better SIAH inhibitors to effectively shut down RAS-dependent signaling transmission in vivo, we aim to use the Drosophila eye, PNS, and salivary gland development as a model system and a rapid drug screening platform to test lead compounds and validate the efficacy of the next-generation anti-SIAH-based anti-K-RAS targeted gene therapy.…”