Combined inhibition of HMGCoA reductase and mitochondrial complex I induces tumor regression of BRAF inhibitor-resistant melanomas

Abstract

Background Primary and posttreatment resistance to BRAFV600 mutation–targeting inhibitors leads to disease relapse in a majority of melanoma patients. In many instances, this resistance is promoted by upregulation of mitochondrial oxidative phosphorylation (OxPhos) in melanoma cells. We recently showed that a novel electron transport chain (ETC) complex I inhibitor, IACS-010759 (IACS), abolished OxPhos and significantly inhibited tumor growth of high-OxPhos, BRAF inhibitor (BRAFi)–resistant human melanomas. However, the inhibition was not uniform across different high OxPhos melanomas, and combination with BRAFi did not improve efficacy. Methods We performed a high-throughput unbiased combinatorial drug screen of clinically relevant small molecules to identify the most potent combination agent with IACS for inhibiting the growth of high-OxPhos, BRAFi-resistant melanomas. We performed bioenergetics and carbon-13 metabolite tracing to delineate the metabolic basis of sensitization of melanomas to the combination treatment. We performed xenograft tumor growth studies and Reverse-Phase Protein Array (RPPA)–based functional proteomics analysis of tumors from mice fed with regular or high-fat diet to evaluate in vivo molecular basis of sensitization to the combination treatment. Results A combinatorial drug screen and subsequent validation studies identified Atorvastatin (STN), a hydroxymethylglutaryl-coenzyme A reductase inhibitor (HMGCRi), as the most potent treatment combination with IACS to inhibit in vitro cell growth and induce tumor regression or stasis of some BRAFi-resistant melanomas. Bioenergetics analysis revealed a dependence on fatty acid metabolism in melanomas that responded to the combination treatment. RPPA analysis and carbon-13 tracing analysis in these melanoma cells showed that IACS treatment decreased metabolic fuel utilization for fatty acid metabolism, but increased substrate availability for activation of the mevalonate pathway by HMGCR, creating a dependence on this pathway. Functional proteomic analysis showed that IACS treatment inhibited MAPK but activated AKT pathway. Combination treatment with STN counteracted AKT activation. Conclusions STN and other clinically approved HMGCRi could be promising combinatorial agents for improving the efficacy of ETC inhibitors like IACS in BRAFi-resistant melanomas.

Ketogenic diets slow melanoma growth in vivo regardless of tumor genetics and metabolic plasticity

“…In contrast, Xia et al randomized mice to dietary intervention groups 1 week before tumor initiation [ 4 ]. Consistent with our data, de Groot et al demonstrated reduced tumor growth of BRAF-inhibitor-sensitive and BRAF-inhibitor-resistant A375 melanoma xenografts in mice fed with KD [ 6 ]. Interestingly, the authors used exactly the same KD as Xia et al but started KD intervention after tumor cell injection as we did.…”

“…In contrast, a KD successfully enhanced immune checkpoint therapy in an immunocompetent transgenic melanoma mouse model [ 5 ]. Moreover, another study reported reduced tumor growth of BRAF-inhibitor-sensitive as well as BRAF-inhibitor-resistant human melanoma xenografts induced by a KD [ 6 ]. Since cutaneous melanoma is the major cause of skin-cancer-related death and one of the most frequently metastasizing and drug-resistant types of solid tumor [ 7 ], it is essential to clarify the efficacy of KDs as an adjunct cancer therapy.…”

A traditional gynecological medicine inhibits ovarian cancer progression and eliminates cancer stem cells via the LRPPRC–OXPHOS axis

“…Attempts in OXPHOS-targeted therapy so far have mainly focused on either directly suppressing the activity of OXPHOS complexes or inhibiting key enzymes in the tricarboxylic acid cycle (TCA, the metabolic pathway providing reducing equivalents and electrons for OXPHOS), such as metformin [16], buformin [17], and IACS-010759 [18]. However, as non-transformed cells also depend on OXPHOS, such inhibitors also affect the metabolism of normal cells, leading to toxic and side effects.…”

Proteomics as a tool to improve novel insights into skin diseases: what we know and where we should be going

“…Among 28 studies related to skin cancer therapy, 19 studies used in vitro cells, and 89.473% were tumor cell lines. For samples, de Groot et al have reported that combined treatment of IACS-010759 (IACS) and atorvastatin (STN) could induce tumor regression, and they further explored the mechanism MAPK pathway using functional proteomic analysis (50). In researching glucocorticoid treatment for vitiligo, Qian et al pioneered urine as a sample source for proteomics to identify the differentially expressed proteins and ingenuity pathway analysis (such as retinol binding protein-1 and torsin 1A interacting protein 1) (51).…”