Ohanna et al. show that in BRAFV600E melanoma cells, NAMPT expression induces transcriptomic and epigenetic reshufflings that steers melanoma cells toward an invasive phenotype associated with resistance to targeted therapies and immunotherapies.,In BRAFV600E melanoma cells, a global metabolomic analysis discloses a decrease in nicotinamide adenine dinucleotide (NAD+) levels upon PLX4032 treatment that is conveyed by a STAT5 inhibition and a transcriptional regulation of the nicotinamide phosphoribosyltransferase (NAMPT) gene.,NAMPT inhibition decreases melanoma cell proliferation both in vitro and in vivo, while forced NAMPT expression renders melanoma cells resistant to PLX4032.,NAMPT expression induces transcriptomic and epigenetic reshufflings that steer melanoma cells toward an invasive phenotype associated with resistance to targeted therapies and immunotherapies.,Therefore, NAMPT, the key enzyme in the NAD+ salvage pathway, appears as a rational target in targeted therapy-resistant melanoma cells and a key player in phenotypic plasticity of melanoma cells.
Drug resistance invariably limits the clinical efficacy of targeted therapy with kinase inhibitors against cancer1,2.,Here we show that targeted therapy with BRAF, ALK, or EGFR kinase inhibitors induces a complex network of secreted signals in drug-stressed melanoma and lung adenocarcinoma cells.,This therapy-induced secretome (TIS) stimulates the outgrowth, dissemination, and metastasis of drug-resistant cancer cell clones and supports the survival of drug-sensitive cancer cells, contributing to incomplete tumour regression.,The vemurafenib reactive secretome in melanoma is driven by down-regulation of the transcription factor FRA1.,In situ transcriptome analysis of drug-resistant melanoma cells responding to the regressing tumour microenvironment revealed hyperactivation of multiple signalling pathways, most prominently the AKT pathway.,Dual inhibition of RAF and PI3K/AKT/mTOR pathways blunted the outgrowth of the drug-resistant cell population in BRAF mutant melanoma tumours, suggesting this combination therapy as a strategy against tumour relapse.,Thus, therapeutic inhibition of oncogenic drivers induces vast secretome changes in drug-sensitive cancer cells, paradoxically establishing a tumour microenvironment that supports the expansion of drug-resistant clones, but is susceptible to combination therapy.