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Monitoring of melanoma patients on treatment reveals a distinct macrophage population driving targeted therapy resistance

ABSTRACT: Resistance to targeted therapy remains a major clinical challenge in melanoma patients. To uncover resistance mechanisms, we performed single cell RNA sequencing of fine needle aspirates from resistant and responding tumors from melanoma patients before and during BRAFi/MEKi treatment. Among the genes most differentially expressed between malignant cells from resistant vs. responding tumors was POSTN encoding the secreted factor periostin. POSTN was predicted to predominantly signal to a macrophage population associated with targeted therapy resistance (TTR). Accordingly, tumors from patients with fast disease progression after targeted therapy exhibited high POSTN expression levels as well as high numbers of TTR macrophages, and POSTN was able to polarize macrophages towards a TTR phenotype. In a mouse model in vivo, POSTN expression protected melanoma from targeted therapy, which was associated with a phenotype change of intratumroal macrophages. Finally, polarized TTR macrophages protected melanoma cells from MEKi-induced killing through CD44 receptor expression on melanoma cells. Thus, interfering with the protective activity of TTR macrophages might represent a strategy to overcome resistance to targeted therapy in melanoma.

ORGANISM(S): Homo sapiens

PROVIDER: GSE262779 | GEO | 2024/05/08

REPOSITORIES: GEO

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Project description:Nearly 50% of cutaneous melanomas carry activating mutations on the BRAF oncogene, and the combination of BRAF- and MEK-inhibitors (BRAF/MEKi) is frequently used for their clinical management. One major drawback of BRAF/MEKi targeted therapy is the rapid development of therapeutic resistance, which can occur via multiple mechanisms, including the metabolic rewiring of cancer cells that often involves the upregulation of mitochondrial bionergetics and NAD+ biosynthetic pathways. mTORC2 is a signaling complex that requires the presence of its essential RICTOR subunit to play its regulatory functions in cell growth and metabolism. mTORC2 is believed to play mostly pro-oncogenic roles in several tumor types, including melanoma. However, bioinformatics analysis of TCGA melanoma patients’ database revealed that low RICTOR levels in tumors correlate with an overall worse clinical outcome. GSEA analysis of low-RICTOR tumors evidenced also a gene expression signature suggestive of activation of mitochondrial energy producing pathways. On these bases, we have hypothesized that inhibition of mTORC2 activity may render BRAFV600E melanoma cells resistant to BRAFi/MEKi. We show here that RICTOR/mTORC2-deficient cells are intrinsically tolerant to BRAFi/MEKi, and anticipate the onset of resistance to BRAFi after sustained drug exposure both in vitro and in vivo, indicating that mTORC2 activity normally opposes the acquisition of targeted therapy resistance in BRAFV600E melanomas. Mechanistically, RICTOR-deficient cells show an enhanced mitochondrial respiratory potential and increased expression of nicotinamide phosphoribosyltransferase (NAMPT) protein, the rate-limiting enzyme of NAD+ salvage pathway, and pharmacological inhibition of these processes in RICTOR-deficient cells is sufficient to restore sensitivity to BRAFi. Thus, our work identifies a novel role for mTORC2 in favoring the responses of BRAF-mutated melanoma cells to targeted therapy, and suggest that the evaluation of the intratumor level of RICTOR may help to predict the responses of melanoma patients to these treatments.

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Monitoring of melanoma patients on treatment reveals a distinct macrophage population driving targeted therapy resistance

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